Fluorene compound and pharmaceutical use thereof

ABSTRACT

The present invention provides an agent for the prophylactic or treatment of diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like. A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof: 
                         
wherein each symbol is as defined in the specification.

This patent claims the benefit of priority of U.S. ProvisionalApplication No. 61/196,290, filed Oct. 16, 2008; U.S. ProvisionalApplication No. 61/276,772, filed Sep. 16, 2009; and Japanese PatentApplication Nos. 2008-264681, filed Oct. 10, 2008 and 2009-209855, filedon Sep. 10, 2009, all of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a fluorene compound and apharmaceutical use thereof. More particularly, the present inventionrelates to a compound for the prophylaxis or treatment of diabetes,cardiovascular diseases, hyperlactacidemia and cancer based onactivation of pyruvate dehydrogenase (PDH) by inhibition of pyruvatedehydrogenase kinase (PDHK), and use thereof. Furthermore, the presentinvention relates to a compound for the prophylaxis or treatment ofdiabetic complications (e.g., neuropathy, retinopathy, nephropathy,cataract etc.), brain ischemia, cerebral apoplexy or pulmonaryhypertension, and use thereof.

BACKGROUND OF THE INVENTION

In tissue, for reaction using energy, for example, biosynthesis, activebiological transport, muscle contraction etc., the energy is supplied byhydrolysis of adenosine triphosphate (ATP). ATP is produced by oxidationof metabolic fuel which yields much energy, such as glucose and freefatty acids. In oxidative tissues such as muscle, ATP is mostly producedfrom acetyl-CoA that enters citric acid cycle. Acetyl-CoA is produced byoxidation of glucose via glycolytic pathway or β oxidation of free fattyacid. An enzyme that plays a pivotal role in controlling acetyl-CoAproduction from glucose is PDH. PDH catalyses the oxidation of pyruvateto acetyl-CoA and carbon dioxide with concomitant reduction ofnicotinamide adenine dinucleotide (NAD) to NADH.

PDH is a multienzyme complex consisting of three enzyme components (E1,E2 and E3) and some subunits localized in mitochondria matrix. E1, E2and E3 are responsible for decarboxylation from pyruvate, production ofacetyl-CoA and reduction of NAD to NADH, respectively. Two classes ofenzyme having regulatory function are associated with the complex. Oneis PDHK, which are protein kinases having specificity to PDH. The rolethereof is to inactivate E1α subunit of the complex by phosphorylation.The other is PDH phosphatases, which are specific protein phosphataseswhich activate PDH via dephosphorylation of E1α subunit. The proportionof PDH in its active (dephosphorylated) state is determined by thebalance of kinase activity and phosphatase activity. The kinase activityis regulated by relative concentrations of metabolic substrates. Forexample, the kinase activity is activated by an increase in theNADH/NAD, acetyl-CoA/CoA or ATP/adenosine diphosphate (ADP) ratios, andinhibited by pyruvate.

Four PDHK isoenzymes have been identified in mammalian tissues.Particularly, PDHK2 is expressed in a wide range of tissues includingthe liver, skeletal muscles and adipose tissues involved in glucosemetabolism. Since it shows comparatively high sensitivity to activationby increased NADH/NAD or acetyl-CoA/CoA and inhibition by pyruvate,involvement in a short-term regulation of glucose metabolism issuggested.

In diseases such as insulin-dependent (type 1) diabetes andnon-insulin-dependent (type 2) diabetes and the like, oxidation oflipids is increased with a concomitant reduction in utilization ofglucose. This is one of the factors causing hyperglycemia. When theoxidative glucose metabolism is reduced in type 1 and type 2 diabetesand obesity, PDH activity is also reduced. It suggests involvement ofreduced PDH activity in the reduced utilization of glucose in type 1 andtype 2 diabetes. On the contrary, hepatic gluconeogenesis is enhanced intype 1 and type 2 diabetes, which also forms one factor causinghyperglycemia. The reduced PDH activity increases pyruvateconcentration, which in turn increases availability of lactate as asubstrate for hepatic gluconeogenesis. It suggests possible involvementof reduced PDH activity in the enhanced gluconeogenesis in type 1 andtype 2 diabetes. When PDH is activated by inhibition of PDHK, the rateof glucose oxidation is considered to rise. As a result, glucoseutilization in the body is promoted and hepatic gluconeogenesis issuppressed, whereby hyperglycemia in type 1 and type 2 diabetes isexpected to be improved. Another factor contributing to diabetes isimpaired insulin secretion, which is known to be associated with reducedPDH activity in pancreatic β cells. It is also known that sustainedhyperglycemia due to diabetes causes complications such as neuropathy,retinopathy, nephropathy, cataract and the like. Thiamine and α-lipoicacid contribute to activation of PDH as coenzymes, and also, they orderivatives thereof have been shown to have a promising effect in thetreatment of diabetic complications. Thus, activation of PDH is expectedto improve diabetic complications.

Under ischemic conditions, limited oxygen supply reduces oxidation ofboth glucose and fatty acid oxidation and reduces the amount of ATPproduced by oxidative phosphorylation in the tissues. In the absence ofsufficient oxygen, ATP level is maintained by promoted anaerobicglycolysis. As a result, lactic acid increases and intracellular pHdecreases. Even though the body tries to maintain homeostasis of ion byenergy consumption, abnormally low ATP level and disrupted cellularosmolarity lead to cell death. In addition, adenosinemonophosphate-activating kinase, activated during ischemia,phosphorylates and thus inactivates acetyl-CoA carboxylase. The levelsof total malonyl-CoA in the tissue drop, carnitinepalmitoyltransferase-I activity is therefore increased and fatty acidoxidation is favored over glucose oxidation by allowing the transport ofacyl-CoA into mitochondria. Oxidation of glucose is capable yieldingmore ATP per mole of oxygen than is oxidation of fatty acids. Underischemic conditions, therefore, when energy metabolism becomes glucoseoxidation dominant by activation of PDH, the ability to maintain ATPlevel is considered to be enhanced. In addition, since activation of PDHcauses oxidation of pyruvate produced by glycolysis, and reducingproduction of loactate, the net proton burden is considered to bereduced in ischemic tissues. Accordingly, PDH activation by inhibitionof PDHK is expected to protectively act in ischemic diseases such ascardiac muscle ischemia.

A drug that activates PDH by inhibition of PDHK is considered todecrease lactate production since it promotes pyruvate metabolism.Hence, such drug is expected to be useful for the treatment ofhyperlactacidemia such as mitochondrial disease, mitochondrialencephalomyopathy and sepsis.

In cancer cells, ATP production by oxidative phosphorylation inmitochondria decreases, and ATP production via the anaerobic glycolysisin cytoplasm increases. PDH activation by inhibition of PDHK is expectedto promote oxidative phosphorylation in mitochondria, which will induceapoptosis of cancer cells. Therefore, the mechanism is useful for thetreatment of cancer diseases. Pulmonary hypertension is characterized byhigh blood pressure caused by partial narrowing of the pulmonary arterydue to promoted cell proliferation therein. In pulmonary hypertension,therefore, activation of PDH in the pulmonary artery cell is expected topromote oxidative phosphorylation in mitochondria, and induce apoptosisof the pulmonary artery cells. Therefore, the mechanism is useful forthe treatment of pulmonary hypertension.

It has been shown that dichloroacetic acid, which is a drug having a PDHactivating action, provides promising effects for amelioration ofhyperglycemia, treatment of myocardial ischemia, treatment ofhyperlactacidemia and treatment of cancer diseases. Moreover, usefulnessof dichloroacetic acid for the treatment of cerebral ischemia, cerebralapoplexy or pulmonary hypertension has been shown.

From the foregoing findings, a PDHK inhibitor is considered to be usefulfor the treatment or prophylaxis of diseases relating to glucoseutilization disorder, for example, diabetes (e.g., type 1 diabetes, type2 diabetes etc.), insulin resistance syndrome, metabolic syndrome,hyperglycemia and hyperlactacidemia. In addition, a PDHK inhibitor isconsidered to be useful for the treatment or prophylaxis of diabeticcomplications (e.g., neuropathy, retinopathy, nephropathy, cataractetc.). Furthermore, a PDHK inhibitor is considered to be useful for thetreatment or prophylaxis of diseases caused by limited energy substratesupply to the tissues, for example, cardiac failure, cardiomyopathy,myocardial ischemia, dyslipidemia and atherosclerosis. Additionally, aPDHK inhibitor is considered to be useful for the treatment orprophylaxis of cerebral ischemia or cerebral apoplexy. Moreover, a PDHKinhibitor is considered to be useful for the treatment or prophylaxis ofmitochondrial disease, mitochondrial encephalomyopathy, cancer and thelike. Also, it is considered to be useful for the treatment orprophylaxis of pulmonary hypertension.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide an agent for the prophylactic ortreatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.),insulin resistance syndrome, metabolic syndrome, hyperglycemia,dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy,myocardial ischemia, hyperlactacidemia, mitochondrial disease,mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor andthe like. Moreover, the present invention aims to provide a PDHKinhibitor also useful as an agent for the prophylactic or treatment ofdiabetic complications (e.g., neuropathy, retinopathy, nephropathy,cataract etc.), brain ischemia, cerebral apoplexy or pulmonaryhypertension, and the like.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt todevelop an agent for the prophylactic or treatment of diabetes (e.g.,type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome,metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis,cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia,mitochondrial disease, mitochondrial encephalomyopathy, cancer, diabeticcomplications (e.g., neuropathy, retinopathy, nephropathy, cataractetc.), brain ischemia, cerebral apoplexy or pulmonary hypertension,which is based on a PDHK inhibitory action and found a fluorene compoundhaving a PDHK inhibitory action, and completed the present invention.

Accordingly, the present invention provides the following.

-   [1] A compound represented by the following formula [I] or a    pharmaceutically acceptable salt thereof, or a solvate thereof.

-   wherein,-   R^(a) is-   (1) a hydrogen atom, or-   (2) a halogen atom;-   R^(b) is-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group A,-   (4) a C₂₋₆ alkenyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group C,-   (5) a C₂₋₆ alkynyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group C,-   (6) a cyano group,-   (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from the following group B, and R^(b13)    is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group B,-   (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B, or-   (16) a group represented by the following formula:

-   wherein-   Y^(b) is-   (i) a single bond,-   (ii) a C₁₋₆ alkylene,-   (iii) a C₂₋₆ alkenylene,-   (iv) —O—(CH₂)_(n1)— wherein n1 is an integer of 0, or 1 to 4,-   (v) —O—(CH₂)_(n2)—C(═O)— wherein n2 is an integer of 0, or 1 to 4,-   (vi) —C(═O)—, or-   (vii) —NR^(b16)— wherein R^(b16) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group B;-   ring T is-   (i) a C₆₋₁₀ aryl group,-   (ii) a C₃₋₁₀ cycloalkyl group,-   (iii) a C₅₋₁₀ bridged cycloalkyl group,-   (iv) a monocyclic aromatic heterocyclic group which contains,    besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms, or-   (v) a monocyclic non-aromatic heterocyclic group which contains,    besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms,-   R^(j) are the same or different and each is a substituent selected    from the following group D, and p is an integer of 0, or 1 to 4;-   R^(c) is-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₆ alkyl group,-   (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atom or a C₁₋₆ alkyl    group,-   (5) —OR^(c2) wherein R^(c2) is a hydrogen atom or a C₁₋₆ alkyl    group,-   (6) —NR^(c3)R^(c4) wherein R^(c3) and R^(c4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group, or-   (7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group;-   X^(d) is-   (1) a nitrogen atom, or-   (2) C—R^(d)-   wherein R^(d) is-   (i) a hydrogen atom,-   (ii) a halogen atom,-   (iii) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group A,-   (iv) a C₂₋₆ alkenyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group C,-   (v) a C₂₋₆ alkynyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group C,-   (vi) a cyano group,-   (vii) —C(═O)—R^(d1) wherein R^(d1) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (viii) —C(═O)—OR^(d2) wherein R^(d2) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (ix) —C(═O)—NR^(d3)R^(d4) wherein R^(d3) and R^(d4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (x) —C(═O)—NR^(d5)—OR^(d6) wherein R^(d5) and R^(d6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (xi) —OR^(d7) wherein R^(d7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (xii) —NR^(d8)R^(d9) wherein R^(d8) and R^(d9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (xiii) —NR^(d10)—C(═O)—R^(d11) wherein R^(d10) and R^(d11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (xiv) —NR^(d12)—C(═O)—OR^(d13) wherein R^(d12) is a hydrogen atom or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from the following group B, and R^(d13)    is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group B,    or-   (xv) a group represented by the following formula:

-   wherein-   Y^(d) is-   (I) a single bond, or-   (II) —C(═O)—,-   ring U is-   (I) a C₆₋₁₀ aryl group,-   (II) a C₃₋₁₀ cycloalkyl group,-   (III) a C₃₋₁₀ bridged cycloalkyl group,-   (IV) a monocyclic aromatic heterocyclic group which contains,    besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms, or-   (V) a monocyclic non-aromatic heterocyclic group which contains,    besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms,-   R^(k) are the same or different and each is a substituent selected    from the following group D, and-   m is an integer of 0, or 1 to 4;-   R^(e) are the same or different and each is,-   (1) a halogen atom, or-   (2) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group C;    and-   n is an integer of 0, or 1 to 3,-   provided when X^(d) is C—R^(d), and R^(d) is a hydrogen atom, at    least one of R^(a), R^(b) and R^(c) is not a hydrogen atom.-   Group A is selected from the group consisting of-   (a) a halogen atom,-   (b) a cyano group,-   (c) —C(═O)—R^(A1) wherein R^(A1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (d) —C(═O)—OR^(A2) wherein R^(A2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (e) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (f) —C(═O)—NR^(A5)—OR^(A6) wherein R^(A5) and R^(A6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (g) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (h) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (i) —NR^(A10)—C(═O)—R^(A11) wherein R^(A10) and R^(A11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group B,-   (j) —NR^(A12)—C(═O)—OR^(A13) wherein R^(A12) is a hydrogen atom or a    C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from the following group B, and R^(A13)    is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group B,-   (k) —S(═O)₂—R^(A14) wherein R^(A14) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group B,-   (l) —S(═O)₂—OR^(A15) wherein R^(A15) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group B, and-   (m) —Si—(CH₂—CH₃)₃.-   Group B is selected from the group consisting of-   (a) a halogen atom,-   (b) a cyano group,-   (c) —C(═O)—R^(B1) wherein R^(B1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group C,-   (d) —C(═O)—OR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group C,-   (e) —C(═O)—NR^(B3)R^(B4) wherein R^(B3) and R^(B4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group C,-   (f) —C(═O)—NR^(B5)—OR^(B6) wherein R^(B5) and R^(B6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group C,-   (g) —OR^(B7) wherein R^(B7) is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group C,-   (h) —NR^(B8)R^(B9) wherein R^(B8) and R^(B9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group C,-   (i) —NR^(B10)—C(═O)—R^(B11) wherein R^(B10) and R^(B11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group C,-   (j) —NR^(B12)—S(═O)₂—R^(B13) wherein R^(B12) and R^(B13) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group C,-   (k) —NR^(B14)—C(═O)—OR^(B15) wherein R^(B14) is a hydrogen atom or a    C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from the following group C, and R^(B15)    is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group C,-   (l) —S(═O)₂—R^(B16) wherein R^(B16) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group C, and-   (m) —S(═O)₂—OR^(B17) wherein R^(B17) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group C.-   Group C is selected from the group consisting of-   (a) a halogen atom,-   (b) —C(═O)—R^(C1) wherein R^(C1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5 halogen    atoms,-   (c) —C(═O)—OR^(C2) wherein R^(C2) is a hydrogen atom or a C₁₋₆ alkyl    group, and-   (d) —OR^(C3) wherein R^(C3) is a hydrogen atom or a C₁₋₆ alkyl    group.-   Group D is selected from the group consisting of-   (a) a halogen atom,-   (b) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group E,-   (c) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally    substituted by the same or different 1 to 5 substituents selected    from the following group F,-   (d) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from the following group F,-   (e) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (f) a C₁₋₆ alkyl group substituted by a monocyclic aromatic    heterocyclic group optionally substituted by the same or different 1    to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group    contains, besides carbon atom, 1 to 4 hetero atoms selected from a    nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms),-   (g) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group F,-   (h) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the    same or different 1 to 5 substituents selected from the following    group F,-   (i) a cyano group,-   (j) —C(═O)—R^(D1) wherein R^(D1) is a hydrogen atom, a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group E, or a monocyclic    non-aromatic heterocyclic group optionally substituted by the same    or different 1 to 5 substituents selected from the following group F    (the monocyclic non-aromatic heterocyclic group contains, besides    carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an    oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting    atoms),-   (k) —C(═O)—OR^(D2) wherein R^(D2) is a hydrogen atom, or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group E, (l)    —C(═O)—NR^(D3)R^(D4) wherein R^(D3) and R^(D4) are the same or    different and each is a hydrogen atom, or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group E,-   (m) —C(═O)—NR^(D5)—OR^(D6) wherein R^(D5) and R^(D6) are the same or    different and each is a hydrogen atom, or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group E,-   (n) —OR^(D7) wherein R^(D7) is a hydrogen atom, or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group E,-   (o) —NR^(D8)R^(D9) wherein R^(D8) and R^(D9) are the same or    different and each is a hydrogen atom, or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group E,-   (p) —NR^(D10)—C(═O)—R^(D11) wherein R^(D10) and R^(D11) are the same    or different and each is a hydrogen atom, or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group E,-   (q) —NR^(D12)—C(═O)—OR^(D13) wherein R^(D12) is a hydrogen atom, or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from the following group E, and R^(D13)    is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group E,-   (r) —S(═O)₂—R^(D14) wherein R^(D14) is a hydrogen atom, or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group E, and-   (s) —S(═O)₂—OR^(D15) wherein R^(D15) is a hydrogen atom, or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group E.-   Group E is selected from the group consisting of-   (a) a halogen atom,-   (b) a cyano group,-   (c) —C(═O)—R^(E1) wherein R^(E1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group F,-   (d) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group F,-   (e) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (f) —C(═O)—NR^(E5)—OR^(E6) wherein R^(E5) and R^(E6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (g) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (h) —NR^(E8)R^(E9) wherein R^(E8) and R^(E9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (i) —NR^(E10)—C(═O)—R^(E11) wherein R^(E10) and R^(E11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (j) —NR^(E12)—C(═O)—OR^(E13) wherein R^(E12) is a hydrogen atom or a    C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from the following group F, and R^(E13)    is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group F,-   (k) —S(═O)₂—R^(E14) wherein R^(E14) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group F,-   (l) —S(═O)₂—OR^(E15) wherein R^(E15) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group F, and-   (m) —NR^(E18)—S(═O)₂—R^(E17) wherein R^(E16) and R^(E17) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group.-   Group F is selected from the group consisting of-   (a) —(CH₂)_(nF1)—C(═O)—OR^(F1) wherein R^(F1) is a hydrogen atom or    a C₁₋₆ alkyl group, and nF1 is an integer of 0, or 1 to 4, and-   (b) —(CH₂)_(nF2)—OR^(F2) wherein R^(F2) is a hydrogen atom or a C₁₋₆    alkyl group, and nF2 is an integer of 0, or 1 to 4.-   [2] The compound of the above-mentioned [1], wherein X^(d) is    C—R^(d) wherein R^(d) is as defined in the above-mentioned [1], or a    pharmaceutically acceptable salt thereof, or a solvate thereof.-   [3] The compound of the above-mentioned [1] or [2], which is    represented by the following formula [II], or a pharmaceutically    acceptable salt thereof, or a solvate thereof.

-   wherein each symbol is as defined in the above-mentioned [1].-   [4] The compound of the above-mentioned [3], wherein ring U is a    monocyclic aromatic heterocyclic group, or a pharmaceutically    acceptable salt thereof, or a solvate thereof.-   [5] The compound of the above-mentioned [3], wherein Y^(d) is a    single bond, or a pharmaceutically acceptable salt thereof, or a    solvate thereof.

[6] The compound of the above-mentioned [4], which is represented by thefollowing formula [III], or a pharmaceutically acceptable salt thereof,or a solvate thereof.

-   wherein-   R^(m) is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or 5    different 1 to 5 substituents selected from group E,-   (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic    heterocyclic group optionally substituted by the same or different 1    to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group    contains, besides carbon atom, 1 to 4 hetero atoms selected from a    nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms),-   (6) a C₃₋₁₀ cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (7) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, and other    symbols are as defined in the above-mentioned [1].-   [7] The compound of the above-mentioned [6], wherein R^(m) is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E′,-   (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, and group E′ is    selected from the group consisting of-   (a) a halogen atom,-   (b) a cyano group,-   (c) —C(═O)—R^(E1) wherein R^(E1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group F,-   (d) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from the following group F,-   (e) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (f) —C(═O)—NR^(E5)—OR^(E6) wherein R^(E5) and R^(E6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (g) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (h) —NR^(E8)R^(E9) wherein R^(E8) and R^(E9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (i) —NR^(E10)—C(═O)—R^(E11) wherein R^(E10) and R^(E11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from the following group F,-   (j) —NR^(E12)—C(═O)—OR^(E13) wherein R^(E12) is a hydrogen atom or a    C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from the following group F, and R^(E13)    is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group F,-   (k) —S(═O)₂—R^(E14) wherein R^(E14) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group F, and-   (l) —S(═O)₂—OR^(E15) wherein R^(E15) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from the following group F,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[8] The compound of the above-mentioned [7], which is represented by thefollowing formula [III-A], or a pharmaceutically acceptable saltthereof, or a solvate thereof.

-   wherein each symbol is as defined in the above-mentioned [7].-   [9] The compound of the above-mentioned [7], wherein R^(c) is a    hydrogen atom, or a pharmaceutically acceptable salt thereof, or a    solvate thereof.

[10] The compound of the above-mentioned [7], wherein R^(b) is

-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A,-   (4) a C₂₋₆ alkenyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (5) a C₂₋₆ alkynyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (6) a cyano group,-   (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B, or-   (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [11] The compound of the above-mentioned [7], wherein R^(a) is a    hydrogen atom, or a pharmaceutically acceptable salt thereof, or a    solvate thereof.-   [12] The compound of the above-mentioned [7], wherein n is 0, or a    pharmaceutically acceptable salt thereof, or a solvate thereof.-   [13] The compound of the above-mentioned [7], wherein R^(m) is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from-   (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group F,-   (ii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (iii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group F, and-   (iv) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (2) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (3) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the    same or different 1 to 5 substituents selected from group F,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [14] The compound of the above-mentioned [7], wherein R^(m) is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from-   (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group F, and-   (ii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group F,-   (2) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (3) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the    same or different 1 to 5 substituents selected from group F,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [15] The compound of the above-mentioned [4], which is represented    by the following formula [VI], or a pharmaceutically acceptable salt    thereof, or a solvate thereof.

-   wherein each symbol is as defined in the above-mentioned [4].-   [16] The compound of the above-mentioned [1], which is represented    by the following formula, or a pharmaceutically acceptable salt    thereof, or a solvate thereof.

-   [17] The compound of the above-mentioned [1], which is represented    by the following formula, or a pharmaceutically acceptable salt    thereof, or a solvate thereof.

-   [18] A pharmaceutical composition comprising the compound of any one    of the above-mentioned [1] to [17], or a pharmaceutically acceptable    salt thereof, or a solvate thereof, and a pharmaceutically    acceptable carrier.-   [19] A PDHK inhibitor comprising the compound of any one of the    above-mentioned [1] to [17], or a pharmaceutically acceptable salt    thereof, or a solvate thereof.-   [20] A PDH activator comprising the compound of any one of the    above-mentioned [1] to [17], or a pharmaceutically acceptable salt    thereof, or a solvate thereof.-   [21] A PDHK2 inhibitor comprising the compound of any one of the    above-mentioned [1] to [17], or a pharmaceutically acceptable salt    thereof, or a solvate thereof.-   [22] A blood glucose level-lowering agent comprising the compound of    any one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof.-   [23] A lactate level-lowering agent comprising the compound of any    one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof.-   [24] An agent for the treatment or prophylaxis of diabetes (e.g.,    type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome,    metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis,    cardiac failure, cardiomyopathy, myocardial ischemia,    hyperlactacidemia, mitochondrial disease, mitochondrial    encephalomyopathy or cancer, comprising the compound of any one of    the above-mentioned [1] to [17], or a pharmaceutically acceptable    salt thereof, or a solvate thereof.-   [25] An agent for the treatment or prophylaxis of diabetes (e.g.,    type 1 diabetes, type 2 diabetes etc.), diabetic complications    (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin    resistance syndrome, metabolic syndrome, hyperglycemia,    dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy,    myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary    hypertension, hyperlactacidemia, mitochondrial disease,    mitochondrial encephalomyopathy or cancer, comprising the compound    of any one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof.-   [26] A method of inhibiting PDHK in a mammal, comprising    administering a pharmaceutically effective amount of the compound of    any one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof to the mammal.-   [27] A method of activating PDH in a mammal, comprising    administering a pharmaceutically effective amount of the compound of    any one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof to the mammal.-   [28] A method of inhibiting PDHK2 in a mammal, comprising    administering a pharmaceutically effective amount of the compound of    any one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof to the mammal.-   [29] A method of decreasing the blood glucose level in a mammal,    comprising administering a pharmaceutically effective amount of the    compound of any one of the above-mentioned [1] to [17], or a    pharmaceutically acceptable salt thereof, or a solvate thereof to    the mammal.-   [30] A method of decreasing lactate level in a mammal, comprising    administering a pharmaceutically effective amount of the compound of    any one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof to the mammal.-   [31] A method for the treatment or prophylaxis of diabetes (e.g.,    type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome,    metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis,    cardiac failure, cardiomyopathy, myocardial ischemia,    hyperlactacidemia, mitochondrial disease, mitochondrial    encephalomyopathy or cancer in mammal, comprising administering a    pharmaceutically effective amount of the compound of any one of the    above-mentioned [1] to [17], or a pharmaceutically acceptable salt    thereof, or a solvate thereof to the mammal.-   [32] A method for the treatment or prophylaxis of diabetes (e.g.,    type 1 diabetes, type 2 diabetes etc.), diabetic complications    (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin    resistance syndrome, metabolic syndrome, hyperglycemia,    dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy,    myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary    hypertension, hyperlactacidemia, mitochondrial disease,    mitochondrial encephalomyopathy or cancer in mammal, comprising    administering a pharmaceutically effective amount of the compound of    any one of the above-mentioned [1] to [17], or a pharmaceutically    acceptable salt thereof, or a solvate thereof to the mammal.-   [33] Use of the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof for the production of a PDHK inhibitor.-   [34] Use of the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof for the production of a PDH activator.-   [35] Use of the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof for the production of a PDHK2 inhibitor.-   [36] Use of the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof for the production of a blood glucose level-lowering agent.-   [37] Use of the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof for the production of a lactate level-lowering agent.-   [38] Use of the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof for the production of an agent for the treatment or    prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes    etc.), insulin resistance syndrome, metabolic syndrome,    hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,    cardiomyopathy, myocardial ischemia, hyperlactacidemia,    mitochondrial disease, mitochondrial encephalomyopathy or cancer.-   [39] Use of the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof for the production of an agent for the treatment or    prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes    etc.), diabetic complications (e.g., neuropathy, retinopathy,    nephropathy, cataract etc.), insulin resistance syndrome, metabolic    syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac    failure, cardiomyopathy, myocardial ischemia, brain ischemia,    cerebral apoplexy, pulmonary hypertension, hyperlactacidemia,    mitochondrial disease, mitochondrial encephalomyopathy or cancer.-   [40] A commercial kit comprising (a) a pharmaceutical composition    comprising the compound of any one of the above-mentioned [1] to    [17], or a pharmaceutically acceptable salt thereof, or a solvate    thereof as active ingredient, and (b) a written matter stating that    the pharmaceutical composition can or should be used for the    treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2    diabetes etc.), diabetic complications (e.g., neuropathy,    retinopathy, nephropathy, cataract etc.), insulin resistance    syndrome, metabolic syndrome, hyperglycemia, dyslipidemia,    atherosclerosis, cardiac failure, cardiomyopathy, myocardial    ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension,    hyperlactacidemia, mitochondrial disease, mitochondrial    encephalomyopathy or cancer.-   [41] A commercial package comprising (a) a pharmaceutical    composition comprising the compound of any one of the    above-mentioned [1] to [17], or a pharmaceutically acceptable salt    thereof, or a solvate thereof as active ingredient, and (b) a    written matter stating that the pharmaceutical composition can or    should be used for the treatment or prophylaxis of diabetes (e.g.,    type 1 diabetes, type 2 diabetes etc.), diabetic complications    (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin    resistance syndrome, metabolic syndrome, hyperglycemia,    dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy,    myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary    hypertension, hyperlactacidemia, mitochondrial disease,    mitochondrial encephalomyopathy or cancer.

Effect of the Invention

Since the fluorene compound of the present invention effectivelyinhibits the PDHK activity, and further, has preferable properties as adrug such as chemical stability and the like, it is effective as anagent for the prophylaxis or treatment of diabetes (e.g., type 1diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolicsyndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrialdisease, mitochondrial encephalomyopathy or cancer, and the like.Furthermore, the fluorene compound of the present invention is alsoeffective as an agent for the prophylaxis or treatment of diabeticcomplications (e.g., neuropathy, retinopathy, nephropathy, cataractetc.), brain ischemia, cerebral apoplexy or pulmonary hypertension.

EMBODIMENT OF THE INVENTION

The present invention is explained in detail in the following.

The definitions of the terms used in the present specification are asfollows.

The “optionally substituted” includes both being substituted atsubstitutable position(s) of an object group and being unsubstituted.Here, the “unsubstituted” means that all substitutable positions of anobject group are occupied by hydrogen atoms.

For example, a “C₁₋₆ alkyl group optionally substituted by the same ordifferent 1 to 5 substituents selected from group A” means both when thesubstitutable position(s) of a C₁₋₆ alkyl group is(are) substituted bythe same or different 1 to 5 substituents selected from group A, andis(are) not substituted (unsubstituted).

Examples of the “halogen atom” include a fluorine atom, a chlorine atom,a bromine atom, an iodine atom and the like.

The “C₁₋₆ alkyl group” means a straight chain or branched chainsaturated hydrocarbon group having 1 to 6 carbon atoms. Examples thereofinclude a methyl group, an ethyl group, a propyl group, an isopropylgroup, a butyl group, an isobutyl group, a sec-butyl group, a tert-butylgroup, a pentyl group, an isopentyl group, a neopentyl group, a1-ethylpropyl group, a hexyl group, an isohexyl group, a1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutylgroup, a 2-ethylbutyl group and the like. Preferred are a methyl group,an ethyl group, a propyl group, an isopropyl group, a butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group,an isopentyl group, a neopentyl group, a hexyl group, an isohexyl group,a 3,3-dimethylbutyl group and the like.

The “C₂₋₆ alkenyl group” means a linear or branched chain unsaturatedhydrocarbon group having 2 to 6 a carbon atoms and containing one ormore double bonds. Examples thereof include a vinyl group, a1-methylvinyl group, a 1-propenyl group, an allyl group, amethylpropenyl group (1-methyl-1-propenyl group, 2-methyl-1-propenylgroup etc.), a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, amethylbutenyl group (1-methyl-1-butenyl group, a 2-methyl-1-butenylgroup, a 3-methyl-1-butenyl group etc.), a pentenyl group, amethylpentenyl group, a hexenyl group and the like. Preferred are avinyl group, a 1-methylvinyl group, a 1-propenyl group, a methylpropenylgroup and the like.

The “C₂₋₆ alkynyl group” means a linear or branched chain unsaturatedhydrocarbon group having 2 to 6 a carbon atoms and containing one ormore triple bonds. Examples thereof include an ethynyl group, a propynylgroup (1-propynyl group, 2-propynyl group), a butynyl group, a pentynylgroup, a hexynyl group and the like. Preferred are an ethynyl group, a1-propynyl group and the like.

The “C₁₋₆ alkylene” means a divalent group derived from theabove-mentioned “C₁₋₆ alkyl group”. Examples thereof include methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethyleneand the like. Preferred are methylene, ethylene, trimethylene and thelike.

The “C₂₋₆ alkenylene” means a divalent group derived from theabove-mentioned “C₂₋₆ alkenyl group”. Examples thereof include vinylene,propenylene, butenylene, pentenylene, hexenylene and the like. Preferredare vinylene and the like.

The “C₆₋₁₀ aryl group” means an aromatic hydrocarbon group having 6 to10 carbon atoms. Examples thereof include a phenyl group, a 1-naphthylgroup, a 2-naphthyl group and the like. Preferred is a phenyl group.

The “C₃₋₁₀ cycloalkyl group” means a monocycle saturated hydrocarbongroup having 3 to 10 carbon atoms. Examples thereof include acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group, a cyclooctyl group and the like.Particularly, a C₃₋₆ cycloalkyl group (e.g., a cyclopropyl group, acyclobutyl group, a cyclopentyl group, a cyclohexyl group etc.) ispreferable.

The “C₅₋₁₀ bridged cycloalkyl group” means a bridged cyclic saturatedhydrocarbon group having 5 to 10 carbon atoms. Examples thereof includea bicyclopentanyl group, a bicyclohexyl group, a bicycloheptyl group, atricycloheptyl group, a bicyclooctyl group, an adamantyl group and thelike. Particularly, an adamantyl group is preferable.

The “monocyclic aromatic heterocyclic group” means a monocyclic aromaticheterocyclic group, containing, besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom, andhaving 3 to 7 ring-constituting atoms. Examples thereof include a furylgroup, a thienyl group, a pyrrolyl group, an oxazolyl group, anisoxazolyl group, a thiazolyl group, an isothiazolyl group, animidazolyl group, a pyrazolyl group, an oxadiazolyl group(1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolylgroup), a thiadiazolyl group (1,2,5-thiadiazolyl group,1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group), a triazolyl group(1,2,3-triazolyl group, 1,2,4-triazolyl group), a tetrazolyl group, apyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinylgroup, a triazinyl group and the like. Preferred are a thienyl group, anoxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolylgroup, an oxadiazolyl group (1,3,4-oxadiazolyl group, 1,2,4-oxadiazolylgroup), a triazolyl group (1,2,4-triazolyl group), a tetrazolyl group, apyridyl group, a pyrimidinyl group and the like.

The “monocyclic non-aromatic heterocyclic group” means a monocyclicsaturated or partially unsaturated heterocyclic group, which contains,besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom,an oxygen atom and a sulfur atom, and has 3 to 7 ring-constitutingatoms. Examples thereof include an oxiranyl group, a thioranyl group, anaziridinyl group, an azetidinyl group, an oxetanyl group, a pyrrolidinylgroup, a pyrrolidino group (1-pyrrolidinyl group), a tetrahydrofuranylgroup, a tetrahydrothienyl group, an oxazolinyl group, an oxazolidinylgroup, an isoxazolinyl group, an isoxazolidinyl group, a thiazolinylgroup, a thiazolidinyl group, an isothiazolinyl group, anisothiazolidinyl group, an imidazolinyl group, an imidazolidinyl group,a pyrazolinyl group, a pyrazolidinyl group, a piperidinyl group, apiperidino group (1-piperidinyl group), a morpholinyl group, amorpholino group (4-morpholinyl group), a thiomorpholinyl group, athiomorpholino group (4-thiomorpholinyl group), a piperazinyl group, apiperazino group (1-piperazinyl group), a hexahydro-1,3-oxazinyl groupand the like. The group may have 1 or 2 oxo groups. In addition, whenthe group contains a sulfur atom as a hetero atom, the sulfur atom maybe mono- or dioxide.

Particularly, an aziridinyl group, an azetidinyl group, a pyrrolidinylgroup, a 2-oxopyrrolidinyl group, a 2-oxopyrrolidino group, anoxazolidinyl group, a 2-oxooxazolidinyl group, an isothiazolidinylgroup, a 1,1-dioxoisothiazolidinyl group, an imidazolidinyl group, a2-oxoimidazolidinyl group, a 2-oxopiperidinyl group, a 2-oxopiperidinogroup, a morpholinyl group, a morpholino group, a 2-oxomorpholino group,a piperazinyl group, a piperazino group, a 2-oxopiperazino group, ahexahydro-2-oxo-1,3-oxazinyl group and the like are preferable.

The “—C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same ordifferent and each is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromgroup B” in the specification is represented by the following formula

-   wherein R^(b3) and R^(b4) are the same or different and each is a    hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the    same or different 1 to 5 substituents selected from group B.

Specific examples thereof include

Furthermore, the “—C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) arethe same or different and each is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from group B” is represented by the following formula

-   wherein R^(b5) and R^(b6) are the same or different and each is a    hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the    same or different 1 to 5 substituents selected from group B.

Specific examples thereof include

Preferable embodiment of each group of the compound represented by theformula [I] (hereinafter to be sometimes abbreviated as compound [I]) isexplained in the following.

-   R^(a)

R^(a) is (1) a hydrogen atom, or (2) a halogen atom, preferably, ahydrogen atom, a fluorine atom or a chlorine atom, more preferably, ahydrogen atom.

-   R^(b)

Preferable embodiments of R^(b) are classified into the following type Aand type B.

-   [type A]

A type wherein R^(b) is a group represented by the following formula:

-   wherein each symbol is as defined above. When X^(d) is C—R^(d),    compound [I] is represented by the formula [IV]

-   [type B]

A type wherein R^(b) is

-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A,-   (4) a C₂₋₆ alkenyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (5) a C₂₋₆ alkynyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (6) a cyano group,-   (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B, or-   (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B.

Preferable embodiments of type A and type B are explained in thefollowing.

-   [type A]

As Y^(b), preferred is

-   (i) a single bond,-   (ii) a C₁₋₃ alkylene (particularly, methylene, trimethylene),-   (iii) a C₂₋₃ alkenylene (particularly, vinylene),-   (iv) —O—(CH₂)_(n1)— wherein n1 is an integer of 0, or 1 to 4    (particularly, 0, or 1 to 3),-   (v) —O—(CH₂)_(n2)—C(═O)— wherein n2 is an integer of 0, or 1 to 4    (particularly, 1),-   (vi) —C(═O)—, or-   (vii) —NR^(b16)— wherein R^(b16) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group);-   more preferably, a single bond, —O—CH₂—, —O—(CH₂)₂—, —O—CH₂—C(═O)—,    or —C(═O)—.

As ring T, preferred is

-   (i) a C₆₋₁₀ aryl group,-   (ii) a C₃₋₆ cycloalkyl group,-   (iii) a C₅₋₁₀ bridged cycloalkyl group,-   (iv) a monocyclic aromatic heterocyclic group which contains,    besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and 5 or 6 ring-constituting    atoms, or-   (v) a monocyclic non-aromatic heterocyclic group which contains,    besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and 3 or 6 ring-constituting    atoms;-   more preferred is-   (i) a phenyl group,-   (ii) a C₃₋₆ cycloalkyl group (particularly, a cyclopropyl group, a    cyclobutyl group, a cyclopentyl group, a cyclohexyl group),-   (iii) an adamantyl group,-   (iv) a monocyclic aromatic heterocyclic group selected from a    thiazolyl group, a pyridyl group, a thienyl group, an oxazolyl    group, a 1,2,4-oxadiazolyl group, a pyrazolyl group, a tetrazolyl    group, and a pyrimidinyl group, or-   (v) a monocyclic non-aromatic heterocyclic group selected from a    piperidino group, a pyrrolidino group, an azetidinyl group, an    aziridinyl group, a morpholino group, a piperazino group, a    2-oxopyrrolidino group, a 2-oxopiperidino group, a    2-oxopyrrolidin-5-yl group, a 2-oxo-1,3-oxazolidin-3-yl group, a    3-oxomorpholino group, a 1,1-dioxoisothiazolidinyl group, a    2-oxoimidazolidinyl group and a hexahydro-2-oxo-1,3-oxazinyl group.

R^(j) is preferably,

-   (1) a halogen atom,-   (2) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E,-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (4) a cyano group,-   (5) —C(═O)—R^(D1) wherein R^(D1) is a hydrogen atom, a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group E, or a monocyclic non-aromatic    heterocyclic group optionally substituted by the same or different 1    to 5 substituents selected from group F (the monocyclic non-aromatic    heterocyclic group contains, besides carbon atom, 1 to 4 hetero    atoms selected from a nitrogen atom, an oxygen atom and a sulfur    atom, and has 3 to 7 ring-constituting atoms),-   (6) —C(═O)—OR^(D2) wherein R^(D2) is a hydrogen atom, or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from group E,-   (7) —C(═O)—NR^(D3)R^(D4) wherein R^(D3) and R^(D4) are the same or    different and each is a hydrogen atom, or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group E,-   (8) —OR^(D7) wherein R^(D7) is a hydrogen atom, or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group E,-   (9) —NR^(D8)R^(D9) wherein R^(D8) and R^(D9) are the same or    different and each is a hydrogen atom, or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group E, or-   (10) —NR^(D10)—C(═O)—R^(D11) wherein R^(D10) and R^(D11) are the    same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group E,-   more preferably,-   (1) a halogen atom (particularly, a fluorine atom, a chlorine atom),-   (2) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, an isobutyl group, a    tert-butyl group, a neopentyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group E    (particularly, a hydroxy group, a methoxymethoxy group, a carboxyl    group, a carbamoyl group),-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl    (particularly, a cyclohexylmethyl group),-   (4) a cyano group,-   (5) —C(═O)—R^(D1) wherein R^(D1) is a hydrogen atom, a C₁₋₆ alkyl    group (particularly, a methyl group, an ethyl group, an isopropyl    group, a tert-butyl group), or a monocyclic non-aromatic    heterocyclic group which contains besides carbon atom, 1 to 4 hetero    atoms selected from a nitrogen atom, an oxygen atom and a sulfur    atom, and has 3 to 7 ring-constituting atoms (particularly, a    pyrrolidino group, a piperidino group, a 4-hydroxypiperidino group,    a 3-hydroxypyrrolidino group),-   (6) —C(═O)—OR^(D2) wherein R^(D2) is a hydrogen atom, or a C₁₋₆    alkyl group (particularly, a methyl group, an ethyl group, an    isopropyl group, a tert-butyl group),-   (7) —C(═O)—NR^(D3)R^(D4) wherein R^(D3) and R^(D4) are the same or    different and each is a hydrogen atom, or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group),-   (8) —OR^(D7) wherein R^(D7) is a hydrogen atom, or a C₁₋₆ alkyl    group (particularly, a methyl group, an ethyl group, a propyl group)    optionally substituted by the same or different 1 to 5 substituents    selected from group E (particularly, a methoxy group, a carboxy    group, a hydroxy group, a methoxycarbonyl group, a carbamoyl group,    a methylcarbamoyl group, a dimethylcarbamoyl group),-   (9) —NR^(D8)R^(D9) wherein R^(D8) and R^(D9) are the same or    different and each is a hydrogen atom, or a C₁₋₆ alkyl group    (particularly, a methyl group), or-   (10) —NR^(D10)—C(═O)—R^(D11) wherein R^(D10) and R^(D11) are the    same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group    (particularly, a methyl group).

Specifically preferable examples of R^(j) include a fluorine atom, achlorine atom, a methyl group, an ethyl group, an isopropyl group, anisobutyl group, a tert-butyl group, a neopentyl group, a hydroxy group,a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group,a 2-hydroxy-2-methylpropyl group, a carboxymethyl group, acarbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group,a cyclohexylmethyl group, a cyano group, an acetyl group, a propionylgroup, an isobutyryl group, a 2,2-dimethylpropionyl group, apyrrolidinocarbonyl group, a piperidinocarbonyl group, a4-hydroxypiperidinocarbonyl group, a 3-hydroxypyrrolidinocarbonyl group,a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, anisopropoxycarbonyl group, a tert-butoxycarbonyl group, a carbamoylgroup, a methylcarbamoyl group, a dimethylcarbamoyl group, adiethylcarbamoyl group, a methoxy group, an ethoxy group, a propoxygroup, a 2-methoxyethoxy group, a 2-hydroxyethoxy group, acarboxymethoxy group, a methoxycarbonylmethoxy group, a carbamoylmethoxygroup, a methylcarbamoylmethoxy group, a dimethylcarbamoylmethoxy group,an amino group, a methylamino group, a dimethylamino group, anacetylamino group, an N-methyl-N-acetylamino group, a2-(methoxymethoxy)ethyl group and the like.

p is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.

In type A, specifically preferable examples of R^(b) include a phenylgroup, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenylgroup, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenylgroup, a 3,5-dichlorophenyl group, a 2-methylphenyl group, a3-methylphenyl group, a 4-methylphenyl group, a 2-(hydroxymethyl)phenylgroup, a 4-(hydroxymethyl)phenyl group, a 4-hydroxyphenyl group, a2-methoxyphenyl group, a 3-methoxycarbonylphenyl group, a4-methoxyphenyl group, a 3-chloro-4-methoxyphenyl group, a3-chloro-4-methoxycarbonylphenyl group, a 2-carboxyphenyl group, a3-carboxyphenyl group, a 4-carboxyphenyl group, a 2-ethoxycarbonylphenylgroup, a 4-ethoxycarbonylphenyl group, a 4-(tert-butoxycarbonyl)phenylgroup, a 3-carbamoylphenyl group, a 3-(methylcarbamoyl)phenyl group, a3-(dimethylcarbamoyl)phenyl group, a 2-carbamoylphenyl group, a2-(methylcarbamoyl)phenyl group, a 2-(dimethylcarbamoyl)phenyl group, a4-carbamoylphenyl group, a 4-(methylcarbamoyl)phenyl group, a4-(dimethylcarbamoyl)phenyl group, a 3-chloro-4-carboxyphenyl group, a3-chloro-4-carbamoylphenyl group, a 3-chloro-4-(methylcarbamoyl)phenylgroup, a 3-chloro-4-(dimethylcarbamoyl)phenyl group, a 4-aminophenylgroup, a 2-(acetylamino)phenyl group, a 4-(acetylamino)phenyl group, a3-cyanophenyl group, a 4-cyanophenyl group, a benzyl group, a2-phenylethenyl group, a benzoyl group, a phenoxy group, a phenylaminogroup, an N-phenyl-N-methylamino group, a benzyloxy group, a cyclopropylgroup, a cyclohexyl group, a cyclobutoxy group, a cyclopentyloxy group,a cyclohexyloxy group, a cyclobutanecarbonyl group, acyclopentanecarbonyl group, a cyclopropylmethyloxy group, acyclobutylmethyloxy group, a cyclopentylmethyloxy group, acyclohexylmethyloxy group, a 2-(adamantan-1-yl)ethoxy group, a2-(3-hydroxyadamantan-1-yl)ethoxy group, a 2-pyridyl group, a 3-pyridylgroup, a 4-pyridyl group, a 2-thienyl group, a 3-thienyl group, a2-methyl-4-pyridyl group, a 5-pyrimidinyl group, a 5-oxazolyl group, a3-methyl-1,2,4-oxadiazol-5-yl group, a 1-methyl-pyrazol-4-yl group, a1,3,5-trimethyl-pyrazol-4-yl group, a 1-ethyl-pyrazol-4-yl group, a1-isopropyl-pyrazol-4-yl group, a 1-isobutyl-pyrazol-4-yl group, a1-tert-butyl-pyrazol-4-yl group, a 1-neopentyl-pyrazol-4-yl group, a1-carboxymethyl-pyrazol-4-yl group, a 1-(2-hydroxyethyl)-pyrazol-4-ylgroup, a 1-carbamoylmethyl-pyrazol-4-yl group, a1-(2-carboxyethyl)-pyrazol-4-yl group, a1-(2-carbamoylethyl)-pyrazol-4-yl group, a1-(2-hydroxy-2-methylpropyl)-pyrazol-4-yl group, a1-cyclohexylmethyl-pyrazol-4-yl group, a pyrazol-1-yl group, a2-thienylcarbonyl group, a 2-thienylmethyloxy group, apyrazol-1-ylmethyl group, a 3-(2-oxopyrrolidino)propyl group, a3-(tetrazol-5-yl)propoxy group, a 2-oxopyrrolidino group, a pyrrolidinogroup, a piperidino group, a morpholino group, a piperazino group, a2-methylpyrrolidino group, a 3-methylpyrrolidino group, a4-carboxypiperidino group, a 4-methylpiperazino group, a4-acetylpiperazino group, a 4-propionylpiperazino group, a4-isobutyrylpiperazino group, a 4-(2,2-dimethylpropionyl)piperazinogroup, a 4-(tert-butoxycarbonyl)piperazino group, a4-(methoxycarbonyl)piperazino group, a 4-(ethoxycarbonyl)piperazinogroup, a 4-(isopropoxycarbonyl)piperazino group, an aziridinocarbonylgroup, an azetidinocarbonyl group, a piperidinocarbonyl group, apyrrolidinocarbonyl group, a morpholinocarbonyl group, a2-methylazetidinocarbonyl group, a 3-methylazetidinocarbonyl group, a3-hydroxyazetidinocarbonyl group, a 3-hydroxymethylazetidinocarbonylgroup, a 3-methoxyazetidinocarbonyl group, a 3-ethoxyazetidinocarbonylgroup, a 3-propoxyazetidinocarbonyl group, a3-(2-methoxyethoxy)azetidinocarbonyl group, a3-(2-hydroxyethoxy)azetidinocarbonyl group, a3-(carboxymethoxy)azetidinocarbonyl group, a3-(methoxycarbonylmethoxy)azetidinocarbonyl group, a3-(carbamoylmethoxy)azetidinocarbonyl group, a3-(methylcarbamoylmethoxy)azetidinocarbonyl group, a3-(dimethylcarbamoylmethoxy)azetidinocarbonyl group, a2-methoxycarbonylazetidinocarbonyl group, a 2-carboxyazetidinocarbonylgroup, a 2-(ethylcarbamoyl)azetidinocarbonyl group, a2-(propylcarbamoyl)azetidinocarbonyl group, a3-methoxycarbonylazetidinocarbonyl group, a 3-carboxyazetidinocarbonylgroup, a 3-carbamoylazetidinocarbonyl group, a3-(methylcarbamoyl)azetidinocarbonyl group, a3-(dimethylcarbamoyl)azetidinocarbonyl group, a3-dimethylaminoazetidinocarbonyl group, a3-(diethylcarbamoyl)azetidinocarbonyl group, a3-(pyrrolidinocarbonyl)azetidinocarbonyl group, a3-(3-hydroxypyrrolidinocarbonyl)azetidinocarbonyl group, a3-(piperidinocarbonyl)azetidinocarbonyl group, a3-(4-hydroxypiperidinocarbonyl)azetidinocarbonyl group, a2-methylpyrrolidinocarbonyl group, a 3-hydroxypyrrolidinocarbonyl group,a 2-methoxycarbonylpyrrolidinocarbonyl group, a3-methoxycarbonylpyrrolidinocarbonyl group, a2-carboxypyrrolidinocarbonyl group, a 3-carboxypyrrolidinocarbonylgroup, a 2-carbamoylpyrrolidinocarbonyl group, a2-(methylcarbamoyl)pyrrolidinocarbonyl group, a2-(dimethylcarbamoyl)pyrrolidinocarbonyl group, a3-carbamoylpyrrolidinocarbonyl group, a3-(methylcarbamoyl)pyrrolidinocarbonyl group, a3-(dimethylcarbamoyl)pyrrolidinocarbonyl group, a2-(hydroxymethyl)pyrrolidinocarbonyl group, a3-(hydroxymethyl)pyrrolidinocarbonyl group, a3-methylaminopyrrolidinocarbonyl group, a3-dimethylaminopyrrolidinocarbonyl group, a3-(N-acetyl-N-methylamino)pyrrolidinocarbonyl group, a4-hydroxypiperidinocarbonyl group, a 4-methoxycarbonylpiperidinocarbonylgroup, a 4-methoxycarbonylpiperidino group, a4-ethoxycarbonylpiperidinocarbonyl group, a 4-ethoxycarbonylpiperidinogroup, a 4-carboxypiperidinocarbonyl group, a4-carbamoylpiperidinocarbonyl group, a 4-carbamoylpiperidino group, a4-(methylcarbamoyl)piperidinocarbonyl group, a4-(methylcarbamoyl)piperidino group, a4-(dimethylcarbamoyl)piperidinocarbonyl group, a4-(dimethylcarbamoyl)piperidino group, a4-(hydroxymethyl)piperidinocarbonyl group, a 2-(2-oxopyrrolidino)ethoxygroup, a 2-(5-hydroxymethyl-2-oxopyrrolidino)ethoxy group, a3-(2-oxopyrrolidino)propoxy group, a 2-(2-oxopiperidino)ethoxy group, a3-(2-oxopiperidino)propoxy group, a 2-(2-oxo-1,3-oxazolidin-3-yl)ethoxygroup, a 2-(1,1-dioxoisothiazolidin-2-yl)ethoxy group, a2-(2-oxo-imidazolidin-1-yl)ethoxy group, a2-(hexahydro-2-oxo-1,3-oxazin-3-yl)ethoxy group, a2-(3-oxomorpholino)ethoxy group, a (2-oxopyrrolidin-5-yl)methoxy group,an (1-methyl-2-oxopyrrolidin-5-yl)methoxy group, an(1-(3-hydroxypropyl)-2-oxopyrrolidin-5-yl)methoxy group, an(1-(2-(methoxymethoxy)ethyl)-2-oxopyrrolidin-5-yl)methoxy group, an(1-(2-hydroxyethyl)-2-oxopyrrolidin-5-yl)methoxy group, anazetidinocarbonylmethoxy group, a pyrrolidinocarbonylmethoxy group, apiperidinocarbonylmethoxy group, a morpholinocarbonylmethoxy group, a(3-hydroxyazetidino)carbonylmethoxy group, a(3-hydroxymethylazetidino)carbonylmethoxy group, a(2-hydroxymethylpyrrolidino)carbonylmethoxy group, a(3-hydroxypyrrolidino)carbonylmethoxy group, a(4-hydroxypiperidino)carbonylmethoxy group, a(4-hydroxymethylpiperidino)carbonylmethoxy group and the like.

Specific structural formulas of R^(b) in type A are as follows.

-   [type B]

In type B, preferable examples of R^(b) include

-   (1) a hydrogen atom,-   (2) a halogen atom (particularly, a fluorine atom, a chlorine atom,    a bromine atom),-   (3) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, an isobutyl group, an    isopentyl group, a neopentyl group, a 3,3-dimethylbutyl group)    optionally substituted by the same or different 1 to 5 substituents    selected from group A [particularly,-   (i) —C(═O)—OR^(A2) wherein R^(A2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (ii) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group,-   (iii) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (iv) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   (v) —NR^(A10)—C(═O)—R^(A11) wherein R^(A10) and R^(A11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), and-   (vi) —Si—(CH₂—CH₃)₃]-   (particularly, a hydroxy group, a methoxy group, a carboxy group, a    methoxycarbonyl group, a carbamoyl group, an acetylamino group, a    methylamino group, an N-acetyl-N-methylamino group, a triethylsilyl    group),-   (4) a C₂₋₆ alkenyl group (particularly, a 1-propenyl group, a    2-methyl-1-propenyl group),-   (5) a C₂₋₆ alkynyl group (particularly, an ethynyl group),-   (6) a cyano group,-   (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, a propyl group, a    butyl group) optionally substituted by the same or different 1 to 5    substituents selected from group B (particularly, a hydroxy group),-   (10) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group, an ethyl group, a propyl group,    an isopropyl group, a butyl group, an isobutyl group, a tert-butyl    group, a pentyl group, an isopentyl group, a neopentyl group, a    hexyl group) optionally substituted by the same or different 1 to 5    substituents selected from group B [particularly,-   (i) —C(═O)—OR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group, an ethyl group),-   (ii) —C(═O)—NR^(B3)R^(B4) wherein R^(B3) and R^(B4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group) optionally    substituted by the same or different 1 to 5 substituents selected    from group C (particularly, a hydroxy group, a carboxyl group),-   (iii) —OR^(B7) wherein R^(B7) is a hydrogen atom or a C₁₋₆ alkyl    group,-   (iv) —NR^(B8)R^(B9) wherein R^(B8) and R^(B9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group) optionally substituted by the same or    different 1 to 5 substituents selected from group C (particularly, a    carboxyl group),-   (v) —NR^(B10)—C(═O)—R^(B11) wherein R^(B10) and R^(B11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, an isopropyl group, a    tert-butyl group) optionally substituted by the same or different 1    to 5 substituents selected from group C (particularly, a hydroxy    group, a carboxyl group, a trifluoroacetyl group),-   (vi) —NR^(B12)S(═O)₂—R^(B13) wherein R^(B12) and R^(B13) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), and-   (vii) —NR^(B14)—C(═O)—OR^(B15) wherein R^(B14) is a hydrogen atom or    a C₁₋₆ alkyl group (particularly, a methyl group, a tert-butyl    group), and R^(B15) is a C₁₋₆ alkyl group (particularly, a methyl    group, a tert-butyl group)]-   (particularly, a carboxyl group, a methoxycarbonyl group, an    ethoxycarbonyl group, a hydroxy group, a carbamoyl group, a    methylcarbamoyl group, a dimethylcarbamoyl group, an amino group, a    methylamino group, a dimethylamino group, a tert-butoxycarbonylamino    group, an acetylamino group, an N-tert-butoxycarbonyl-N-methylamino    group, an N-acetyl-N-methylamino group, an    N-hydroxyacetyl-N-methylamino group, an    N-acetyl-N-(2-hydroxyethyl)amino group, an    N-(2-hydroxyethyl)carbamoyl group, an    N-(2-hydroxyethyl)-N-methylcarbamoyl group, an    N,N-bis(2-hydroxyethyl)carbamoyl group, an    N-methyl-N-methanesulfonylamino group, an    N-acetyl-N-(2-carboxyethyl)amino group, an    N-carboxymethyl-N-methylamino group, an    N-carboxymethyl-N-methylcarbamoyl group, an    N-(2-carboxyethyl)-N-methylcarbamoyl group, a    3-(trifluoroacetyl)propionylamino group, an    N-(2,2-dimethylpropionyl)-N-methylamino group, an    N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino group, an    N-(2-hydroxy-2-methylpropionyl)-N-methylamino group),-   (11) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   (12) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), or-   (13) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group).

In type B, specifically preferable examples of R^(b) include, a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, amethyl group, an ethyl group, a propyl group, an isopropyl group, anisobutyl group, a neopentyl group, a 3,3-dimethylbutyl group, ahydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, a2-hydroxy-2-methylpropyl group, a 3-hydroxy-3-methylbutyl group, a4-hydroxy-3,3-dimethylbutyl group, a methoxycarbonylmethyl group, acarboxymethyl group, a carbamoylmethyl group, an acetylaminomethylgroup, a methylaminomethyl group, an N-acetyl-N-methylaminomethyl group,a (triethylsilyl)ethyl group, a 1-propenyl group, a 2-methyl-1-propenylgroup, an ethynyl group, an acetyl group, a carboxyl group, amethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, anethylcarbamoyl group, a propylcarbamoyl group, a dimethylcarbamoylgroup, a diethylcarbamoyl group, an N-methyl-N-ethylcarbamoyl group, anN-(2-hydroxyethyl)carbamoyl group, anN-(2-hydroxyethyl)-N-methylcarbamoyl group, anN-methyl-N-propylcarbamoyl group, an N-(3-hydroxypropyl)carbamoyl group,an N-(3-hydroxypropyl)-N-methylcarbamoyl group, anN-butyl-N-methylcarbamoyl group, an N-(4-hydroxybutyl) carbamoyl group,an N-(4-hydroxybutyl)-N-methylcarbamoyl group, a hydroxy group, amethoxy group, an ethoxy group, a propoxy group, an isopropoxy group, abutoxy group, an isobutoxy group, a pentoxy group, an isopentoxy group,a neopentoxy group, a hexyloxy group, a carboxymethoxy group, amethoxycarbonylmethoxy group, a carbamoylmethoxy group, amethylcarbamoylmethoxy group, a dimethylcarbamoylmethoxy group, a(2-hydroxyethyl)carbamoylmethoxy group, abis(2-hydroxyethyl)carbamoylmethoxy group, anN-(2-hydroxyethyl)-N-methylcarbamoylmethoxy group, anN-carboxymethyl-N-methylcarbamoylmethoxy group, a 2-hydroxyethoxy group,a 2-carboxyethoxy group, a 2-hydroxy-1,1-dimethylethoxy group, a2-carbamoylethoxy group, a 1-carbamoylethoxy group, a2-(methylcarbamoyl)ethoxy group, a 2-(dimethylcarbamoyl)ethoxy group, a2-aminoethoxy group, a 2-(methylamino)ethoxy group, a2-(dimethylamino)ethoxy group, a 2-(tert-butoxycarbonylamino)ethoxygroup, a 2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy group, a2-(acetylamino)ethoxy group, a 2-(N-acetyl-N-methylamino)ethoxy group, a2-(N-hydroxyacetyl-N-methylamino)ethoxy group, a2-(N-acetyl-N-(2-hydroxyethyl)amino)ethoxy group, a2-(N-acetyl-N-methylamino)-1-methylethoxy group, a2-(N-acetyl-N-methylamino)-2-methylethoxy group, a2-(N-methanesulfonyl-N-methylamino)-2-methylethoxy group, a2-(N-methanesulfonyl-N-methylamino)ethoxy group, a2-(N-acetyl-N-(2-carboxyethyl)amino)ethoxy group, a2-(N-carboxymethyl-N-methylamino)ethoxy group, a2-(4-oxo-5,5,5-trifluoropentanoylamino)ethoxy group, a2-(N-(2,2-dimethylpropionyl)-N-methylamino)ethoxy group, a2-(N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino)ethoxy group, a2-(N-(2-methyl-2-hydroxypropionyl)-N-methylamino)ethoxy group, a2-hydroxy-1-(hydroxymethyl)ethoxy group, a 3-hydroxypropoxy group, a3-ethoxycarbonylpropoxy group, a 3-carboxypropoxy group, a3-carbamoylpropoxy group, a 3-(methylcarbamoyl)propoxy group, a3-(dimethylcarbamoyl)propoxy group, a 3-aminopropoxy group, a3-(methylamino)propoxy group, a 3-(dimethylamino)propoxy group, a3-(acetylamino)propoxy group, a 3-(N-acetyl-N-methylamino)propoxy group,a 3-(N-acetyl-N-methylamino)-2-hydroxypropoxy group, a2-(N-acetyl-N-methylamino)propoxy group, a 2,3-dihydroxypropoxy group, a2-(hydroxymethyl)-3-hydroxypropoxy group, a 2-hydroxy-2-methylpropoxygroup, a 3-hydroxy-2,2-dimethylpropoxy group, a 4-hydroxybutoxy group, a4-ethoxycarbonylbutoxy group, a 3-carboxybutoxy group, a 4-carboxybutoxygroup, a 4-carbamoylbutoxy group, a 4-(methylcarbamoyl)butoxy group, a4-(dimethylcarbamoyl)butoxy group, a 5-hydroxypentoxy group, a5-carboxypentoxy group, a 6-hydroxyhexyloxy group, an amino group, adimethylamino group, a methylamino group, an acetylamino group, anN-acetyl-N-methylamino group, a dimethylaminocarbonyloxy group and thelike.

-   R^(c)

R^(c) is

-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₆ alkyl group,-   (4) —C(═O)—OR^(c1) wherein R^(cl) is a hydrogen atom or a C₁₋₆ alkyl    group,-   (5) —OR^(c2) wherein R^(c2) is a hydrogen atom or a C₁₋₆ alkyl    group,-   (6) —NR^(c3)R^(c4) wherein R^(c3) and R^(c4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group, or-   (7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group.

As R^(c), preferred is

-   (1) a hydrogen atom,-   (2) a halogen atom (particularly, a fluorine atom, a chlorine atom),-   (3) a methyl group,-   (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atom or a methyl    group,-   (5) —OR^(c2) wherein R^(c2) is a hydrogen atom, a methyl group or an    ethyl group,-   (6) —NH₂, or-   (7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, an isopropyl group),    particularly preferably, a hydrogen atom.

Specifically preferable examples of R^(c) include a hydrogen atom, afluorine atom, a chlorine atom, a methyl group, a hydroxy group, amethoxy group, an ethoxy group, an amino group, an acetylamino group, apropionylamino group, an isobutyrylamino group, a carboxyl group, amethoxycarbonyl group and the like.

-   X^(d)

Preferable embodiments of X^(d) are classified into the following type Cto type E.

-   [type C]

A type wherein X^(d) is C—R^(d), and R^(d) is a group represented by thefollowing formula:

-   wherein each symbol is as defined above. In this case, compound [I]    is represented by the formula [II]

-   [type D]

A type wherein X^(d) is C—R^(d), and R^(d) is

-   (i) a hydrogen atom,-   (ii) a halogen atom,-   (iii) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A,-   (iv) a C₂₋₆ alkenyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (v) a C₂₋₆ alkynyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (vi) a cyano group,-   (vii) —C(═O)—R^(d1) wherein R^(d1) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (viii) —C(═O)—OR^(d2) wherein R^(d2) is a hydrogen atom or a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (ix) —C(═O)—NR^(d3)R^(d4) wherein R^(d3) and R^(d4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (x) —C(═O)—NR^(d5)—OR^(d6) wherein R^(d5) and R^(d6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (xi) —OR^(d7) wherein R^(d7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (xii) —NR^(d8)R^(d9) wherein R^(d8) and R^(d9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (xiii) —NR^(d10)—C(═O)—R^(d11) wherein R^(d10) and R^(d11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B, or-   (xiv) —NR^(d12)—C(═O)—OR^(d13) wherein R^(d12) is a hydrogen atom or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from group B, and R^(d13) is a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B.-   [type E]

In this type, X^(d) is a nitrogen atom.

In this case, compound [I] is represented by the formula [V]

Preferable embodiment of type C is explained in the following.

-   [type C]

As Y^(d), preferred is

-   (I) a single bond, or-   (II) —C(═O)—,-   more preferred is a single bond.

As ring U, preferred is

-   (I) a C₆₋₁₀ aryl group,-   (II) a C₃₋₁₀ cycloalkyl group,-   (III) a monocyclic aromatic heterocyclic group which contains,    besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms, or-   (IV) a monocyclic non-aromatic heterocyclic group which contains,    besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen    atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms,-   more preferred is-   (I) a phenyl group,-   (II) a cyclopropyl group,-   (III) a monocyclic aromatic heterocyclic group selected from an    oxazolyl group, a pyridyl group, a 1,3,4-oxadiazolyl group, a    1,2,4-oxadiazolyl group, a tetrazolyl group, a pyrazolyl group, a    pyrimidinyl group, a thienyl group, a 1,2,4-triazolyl group, or-   (IV) an aziridinyl group.

R^(k) is preferably

-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E,-   (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic    heterocyclic group optionally substituted by the same or different 1    to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group    contains, besides carbon atom, 1 to 4 hetero atoms selected from a    nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms),-   (6) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (7) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the    same or different 1 to 5 substituents selected from group F, more    preferably,-   (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, a butyl group, an    isobutyl group, a tert-butyl group, a neopentyl group, a    1,1-dimethylpropyl group, a 1-ethylpropyl group, a    1,1,2-trimethylpropyl group) optionally substituted by the same or    different 1 to 5 substituents selected from group E (particularly, a    halogen atom (particularly, a fluorine atom), a hydroxy group, a    carboxyl group, a carbamoyl group, a methylcarbamoyl group, an    ethylcarbamoyl group, an isopropylcarbamoyl group, a    dimethylcarbamoyl group, an acetylamino group, an    N-acetyl-N-methylamino group, a methanesulfonylamino group, a cyano    group),-   (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group    (particularly, a benzyl group),-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl    (particularly, a cyclohexylmethyl group) optionally substituted by    the same or different 1 to 5 substituents selected from group F    (particularly, a hydroxy group),-   (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    (particularly, an adamantan-1-ylmethyl group) optionally substituted    by the same or different 1 to 5 substituents selected from group F    (particularly, a hydroxy group),-   (5) a C₁₋₆ alkyl group (particularly, a propyl group) substituted by    a monocyclic aromatic heterocyclic group which contains, besides    carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an    oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting    atoms (particularly, tetrazolyl) (particularly, a    3-(5-tetrazolyl)propyl group) optionally substituted by the same or    different 1 to 5 C₁₋₆ alkyl groups (particularly, a methyl group),-   (6) a C₃₋₁₀ cycloalkyl group, (particularly, a cyclohexyl group, a    cyclopentyl group) optionally substituted by the same or different 1    to 5 substituents selected from group F (particularly, a    hydroxymethyl group, a carboxyl group),-   (7) a C₅₋₁₀ bridged cycloalkyl group (particularly, a 1-adamantyl    group).

Specifically preferable examples of R^(k) include a methyl group, anethyl group, an isopropyl group, an isobutyl group, a tert-butyl group,a neopentyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a2,3-dihydroxypropyl group, a 2-hydroxy-1-(hydroxymethyl)ethyl group, acarboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethylgroup, an ethylcarbamoylmethyl group, an isopropylcarbamoylmethyl group,a dimethylcarbamoylmethyl group, a 2-carboxyethyl group, a2-carbamoylethyl group, a 2-(methylcarbamoyl)ethyl group, a2-(dimethylcarbamoyl)ethyl group, a 2-(acetylamino)ethyl group, a2-(N-acetyl-N-methylamino)ethyl group, a 2-hydroxy-1,1-dimethylethylgroup, a 2-hydroxy-1-(hydroxymethyl)-1-methylethyl group, a1-carbamoyl-1-methylethyl group, a 1-methylcarbamoyl-1-methylethylgroup, a 1-dimethylcarbamoyl-1-methylethyl group, a2-hydroxy-1,1-bis(hydroxymethyl)ethyl group, a3-hydroxy-2-(hydroxymethyl)propyl group, a 2-hydroxy-2-methylpropylgroup, a 2-hydroxy-1,1,2-trimethylpropyl group, a2-hydroxy-3,3,3-trifluoropropyl group, a 3-methanesulfonylaminopropylgroup, a 3-(5-tetrazolyl)propyl group, a 3-(1-methyl-5-tetrazolyl)propylgroup, a 3-(2-methyl-5-tetrazolyl)propyl group, a1,1-bis(hydroxymethyl)propyl group, a 3-hydroxy-1-(2-hydroxyethyl)propylgroup, a 3-carboxypropyl group, a 4-carboxybutyl group, a1-carboxy-1-methylethyl group, a 2-carboxy-2-methylpropyl group, a2-carboxy-1,1-dimethylethyl group, a cyanomethyl group, a benzyl group,an (1-hydroxycyclohexyl)methyl group, a 3-hydroxyadamantan-1-ylmethylgroup, a 1-hydroxymethylcyclohexyl group, a 1-hydroxymethylcyclopentylgroup, a 1-carboxycyclopentyl group, a 1-adamantyl group and the like.

m is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.

Specifically preferable examples of R^(d) include a phenyl group, acyclopropyl group, a cyclopropanecarbonyl group, an oxazol-5-yl group, a2-methyl-oxazol-5-yl group, an oxazol-2-yl group, a2-(2-hydroxy-1-(hydroxymethyl)ethyl)-oxazol-5-yl group, a 2-pyridylgroup, a 3-pyridyl group, a 4-methyl-3-pyridyl group, a6-methyl-3-pyridyl group, a 4-pyridyl group, a 1,3,4-oxadiazol-2-ylgroup, a 5-methyl-1,3,4-oxadiazol-2-yl group, a3-methyl-1,2,4-oxadiazol-5-yl group, a 5-methyl-1,2,4-oxadiazol-3-ylgroup, a 3-(2-hydroxy-1-(hydroxymethyl)ethyl)-1,2,4-oxadiazol-5-ylgroup, a 2-methyl-5-tetrazolyl group, a 1-methyl-5-tetrazolyl group, apyrazol-4-yl group, a 1-methyl-pyrazol-4-yl group, a1,3,5-trimethyl-pyrazol-4-yl group, a 1-ethyl-pyrazol-4-yl group, a1-isopropyl-pyrazol-4-yl group, a 1-isobutyl-pyrazol-4-yl group, a1-tert-butyl-pyrazol-4-yl group, a 1-neopentyl-pyrazol-4-yl group, a1-benzyl-pyrazol-4-yl group, a 1-(adamantan-1-yl)-pyrazol-4-yl group, a1-(2-hydroxyethyl)-pyrazol-4-yl group, a1-(3-hydroxypropyl)-pyrazol-4-yl group, a1-(2-(acetylamino)ethyl)-pyrazol-4-yl group, a1-(2-(N-acetyl-N-methylamino)ethyl)-pyrazol-4-yl group, a1-carboxymethyl-pyrazol-4-yl group, a 1-carbamoylmethyl-pyrazol-4-ylgroup, a 1-methylcarbamoylmethyl-pyrazol-4-yl group, a1-dimethylcarbamoylmethyl-pyrazol-4-yl group, a1-ethylcarbamoylmethyl-pyrazol-4-yl group, a1-isopropylcarbamoylmethyl-pyrazol-4-yl group, a1-(2-carboxyethyl)-pyrazol-4-yl group, a1-(2-carbamoylethyl)-pyrazol-4-yl group, a1-(2-(methylcarbamoyl)ethyl)-pyrazol-4-yl group, a1-(2-(dimethylcarbamoyl)ethyl)-pyrazol-4-yl group, a1-(3-carboxypropyl)-pyrazol-4-yl group, a1-(4-carboxybutyl)-pyrazol-4-yl group, a 5-pyrimidinyl group, a3-thienyl group, a 3-methyl-1,2,4-triazol-5-yltriazolyl group, a3-methyl-1,2,4-triazol-5-yl group, a1-(1-hydroxycyclohexylmethyl)-pyrazol-4-yl group, a1-(1-(hydroxymethyl)cyclohexyl)-pyrazol-4-yl group, a1-(1-(hydroxymethyl)cyclopentyl)-pyrazol-4-yl group, a1-(1-(3-hydroxyadamantan-1-ylmethyl)-pyrazol-4-yl group, a1-(1-carboxycyclohexyl)-pyrazol-4-yl group, a1-(1-carboxycyclopentyl)-pyrazol-4-yl group, a1-(2,3-dihydroxypropyl)-pyrazol-4-yl group, a1-(1-carboxy-1-methylethyl)-pyrazol-4-yl group, a1-(2-carboxy-2-methylpropyl)-pyrazol-4-yl group, a1-(2-carboxy-1,1-dimethylethyl)-pyrazol-4-yl group, a1-(2-hydroxy-1,1-dimethylethyl)-pyrazol-4-yl group, a1-(2-hydroxy-1-(hydroxymethyl)ethyl)-pyrazol-4-yl group, a1-(2-hydroxy-1-(hydroxymethyl)-1-methylethyl)-pyrazol-4-yl group, a1-(1-carbamoyl-1-methylethyl)-pyrazol-4-yl group, a1-(1-methylcarbamoyl-1-methylethyl)-pyrazol-4-yl group, a1-(1-dimethylcarbamoyl-1-methylethyl)-pyrazol-4-yl group, a1-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)-pyrazol-4-yl group, a1-(3-hydroxy-2-(hydroxymethyl)propyl)-pyrazol-4-yl group, a1-(2-hydroxy-2-methylpropyl)-pyrazol-4-yl group, a1-(2-hydroxy-1,1,2-trimethylpropyl)-pyrazol-4-yl group, a1-(2-hydroxy-3,3,3-trifluoropropyl)-pyrazol-4-yl group, a1-(3-methanesulfonylaminopropyl)-pyrazol-4-yl group, a1-(3-(5-tetrazolyl)propyl)-pyrazol-4-yl group, a1-(3-(1-methyl-5-tetrazolyl)propyl)-pyrazol-4-yl group, a1-(3-(2-methyl-5-tetrazolyl)propyl)-pyrazol-4-yl group, a1-(1,1-bis(hydroxymethyl)propyl)-pyrazol-4-yl group, a1-(3-hydroxy-1-(2-hydroxyethyl)propyl)-pyrazol-4-yl group, anaziridinocarbonyl group and the like.

Ring U is preferably a monocyclic aromatic heterocyclic group.

Furthermore, a compound wherein Y^(d) is a single bond is preferable,and

-   more preferred is a pyrazolyl group (particularly, a pyrazol-4-yl    group) or a pyrimidinyl group (particularly, a pyrimidin-5-yl group)    for ring U.-   Still more preferred is a compound represented by the following    formula, which is a compound wherein ring U is a pyrazol-4-yl group:

-   wherein-   R^(m) is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E,-   (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic    heterocyclic group optionally substituted by the same or different 1    to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group    contains, besides carbon atom, 1 to 4 hetero atoms selected from a    nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms),-   (6) a C₃₋₁₀ cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (7) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, and other    symbols are as defined above.

Here, as R^(m), preferred is

-   (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, a butyl group, an    isobutyl group, a tert-butyl group, a neopentyl group, a    1,1-dimethylpropyl group, a 1-ethylpropyl group, a    1,1,2-trimethylpropyl group) optionally substituted by the same or    different 1 to 5 substituents selected from-   (i) a halogen atom (particularly, a fluorine atom),-   (ii) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆    alkyl group (particularly, a methyl group) optionally substituted by    the same or different 1 to 5 substituents selected from group F,-   (iii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, an isopropyl group)    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (iv) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F,-   (v) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group) optionally substituted by the same or    different 1 to 5 substituents selected from group F, and-   (vi) —NR^(E16)—S(═O)₂—R^(E17) wherein R^(E16) and R^(E17) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group    (particularly, a benzyl group),-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl    (particularly, a cyclohexylmethyl group) optionally substituted by    the same or different 1 to 5 substituents selected from group F    (particularly, a hydroxy group),-   (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    (particularly, an adamantan-1-ylmethyl group) optionally substituted    by the same or different 1 to 5 substituents selected from group F    (particularly, a hydroxy group),-   (5) a C₁₋₆ alkyl group (particularly, a propyl group) substituted by    a monocyclic aromatic heterocyclic group which contains, besides    carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an    oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting    atoms (particularly, tetrazolyl) (particularly, a    3-(5-tetrazolyl)propyl group) optionally substituted by the same or    different 1 to 5 C₁₋₆ alkyl groups (particularly, a methyl group),-   (6) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a    cyclopentyl group) optionally substituted by the same or different 1    to 5 substituents selected from group F (particularly, a hydroxy    group, a hydroxymethyl group, a carboxyl group), and-   (7) a C₅₋₁₀ bridged cycloalkyl group (particularly, an adamantyl    group) optionally substituted by the same or different 1 to 5    substituents selected from group F.

Specifically preferable examples of R^(m) include a methyl group, anethyl group, an isopropyl group, an isobutyl group, a tert-butyl group,a neopentyl group, a 1-benzyl group, an adamantan-1-yl group, a2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-(acetylamino)ethylgroup, a 2-(N-acetyl-N-methylamino)ethyl group, a carboxymethyl group, acarbamoylmethyl group, a methylcarbamoylmethyl group, adimethylcarbamoylmethyl group, an ethylcarbamoylmethyl group, anisopropylcarbamoylmethyl group, a 2-carboxyethyl group, a2-carbamoylethyl group, a 2-(methylcarbamoyl)ethyl group, a2-(dimethylcarbamoyl)ethyl group, a 3-carboxypropyl group, a4-carboxybutyl group, a 1-hydroxycyclohexylmethyl group, a1-(hydroxymethyl)cyclohexyl group, a 1-(hydroxymethyl)cyclopentyl group,a (3-hydroxyadamantan-1-yl)methyl group, a 1-carboxycyclohexyl group, a1-carboxycyclopentyl group, a 2,3-dihydroxypropyl group, a1-carboxy-1-methylethyl group, a 2-carboxy-2-methylpropyl group, a2-carboxy-1,1-dimethylethyl group, a 2-hydroxy-1-(hydroxymethyl)ethylgroup, a 3-hydroxy-2-(hydroxymethyl)propyl group, a2-hydroxy-1,1-dimethylethyl group, a2-hydroxy-1-(hydroxymethyl)-1-methylethyl group, a1-carbamoyl-1-methylethyl group, a 1-methylcarbamoyl-1-methylethylgroup, a 1-dimethylcarbamoyl-1-methylethyl group, a2-hydroxy-1,1-bis(hydroxymethyl)ethyl group, a 2-hydroxy-2-methylpropylgroup, a 2-hydroxy-1,1,2-trimethylpropyl group, a2-hydroxy-3,3,3-trifluoropropyl group, a 3-methanesulfonylaminopropylgroup, a 3-(5-tetrazolyl)propyl group, a 3-(1-methyl-5-tetrazolyl)propylgroup, a 3-(2-methyl-5-tetrazolyl)propyl group, a1,1-bis(hydroxymethyl)propyl group, a 3-hydroxy-1-(2-hydroxyethyl)propylgroup and the like.

In other embodiments, as R^(m), preferred is

-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E′,-   (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, more preferred    is,-   (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, a butyl group, an    isobutyl group, a tent-butyl group, a neopentyl group) optionally    substituted by the same or different 1 to 5 substituents selected    from-   (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F,-   (ii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, an isopropyl group)    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (iii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F, and-   (iv) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group) optionally substituted by the same or    different 1 to 5 substituents selected from group F,-   (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a    cyclopentyl group) optionally substituted by the same or different 1    to 5 substituents selected from group F (particularly, a hydroxy    group, a hydroxymethyl group, a carboxyl group), or-   (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, an adamantyl    group) optionally substituted by the same or different 1 to 5    substituents selected from group F,-   and further preferably,-   (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, a butyl group, an    isobutyl group, a tert-butyl group, a neopentyl group) optionally    substituted by the same or different 1 to 5 substituents selected    from-   (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F, and-   (ii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F,-   (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a    cyclopentyl group) optionally substituted by the same or different 1    to 5 substituents selected from group F (particularly, a hydroxy    group, a hydroxymethyl group, a carboxyl group), or-   (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, a 1-adamantyl    group) optionally substituted by the same or different 1 to 5    substituents selected from group F.

In the above-mentioned formula [III],

-   R^(c) is preferably a hydrogen atom;-   R^(b) is preferably-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A,-   (4) a C₂₋₆ alkenyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (5) a C₂₋₆ alkynyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (6) a cyano group,-   (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B, or-   (15) —O—C(═O)—NR^(b14)R^(b13) wherein R^(b14) and R^(b15) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B;-   R^(a) is preferably a hydrogen atom; and-   n is preferably 0.

In addition, a compound wherein Y^(d) is a single bond and ring U is apyrimidin-5-yl group, which is represented by the following formula:

-   wherein each symbol is as defined above,-   is preferable.

Here, m is preferably 0;

-   R^(a) is preferably a hydrogen atom; and-   n is preferably 0.

In the following, a preferable embodiment of type D is explained.

-   [type D]

R^(d) is preferably

-   (i) a hydrogen atom,-   (ii) a halogen atom (particularly, a fluorine atom, a chlorine atom,    a bromine atom),-   (iii) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A [particularly,-   (1) a halogen atom (particularly, a fluorine atom),-   (2) a cyano group,-   (3) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and e are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group,-   (4) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), and-   (5) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group)] (particularly, a fluorine atom, a    hydroxy group, a methoxy group, an amino group, a cyano group, a    carbamoyl group) (particularly, a methyl group, an ethyl group, an    isopropyl group, a trifluoromethyl group, an aminomethyl group),-   (iv) a C₂₋₆ alkenyl group (particularly, a 1-methylvinyl group),-   (v) a C₂₋₆ alkynyl group (particularly, an ethynyl group, a    3-hydroxy-1-propynyl group) optionally substituted by the same or    different 1 to 5 substituents selected from group C (particularly, a    hydroxy group),-   (vi) a cyano group,-   (vii) —C(═O)—R^(d1) wherein R^(d1) is a hydrogen atom or a C₁₋₆    alkyl group (particularly, a methyl group, an ethyl group, an    isopropyl group),-   (viii) —C(═O)—OR^(d2) wherein R^(d2) is a hydrogen atom or a C₁₋₆    alkyl group (particularly, a methyl group, an ethyl group, a propyl    group, an isopropyl group),-   (ix) —C(═O)—NR^(d3)R^(d4) wherein R^(d3) and R^(d4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   (x) —C(═O)—NR^(d5)—OR^(d6) wherein R^(d5) and R^(d6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   (xi) —OR^(d7) wherein R^(d7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group, an ethyl group),-   (xii) —NR^(d8)R^(d9) wherein R^(d8) and R^(d9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   (xiii) —NR^(d10)—C(═O)—OR^(d11) wherein R^(d10) and R^(d11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), or-   (xiv) —NR^(d12)—C(═O)—OR^(d13) wherein R^(d12) is a hydrogen atom or    a C₁₋₆ alkyl group (particularly, a methyl group), and R^(d13) is a    C₁₋₆ alkyl group (particularly, a methyl group).

In type D, specifically preferable examples of R^(d) include a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group,an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a methoxymethylgroup, a trifluoromethyl group, an aminomethyl group, a cyanomethylgroup, a carboxymethyl group, a carbamoylmethyl group, a 1-methylvinylgroup, an ethynyl group, a 3-hydroxypropynyl group, a cyano group, anacetyl group, a propionyl group, an isobutyryl group, a carboxy group, amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,an isopropoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group,a dimethylcarbamoyl group, an N-methyl-N-methoxycarbamoyl group, ahydroxy group, a methoxy group, an ethoxy group, an amino group, amethylamino group, a dimethylamino group, an acetylamino group, amethoxycarbonylamino group and the like.

As X^(d), type C and type D are preferable, and type C is morepreferable.

-   R^(e)

R^(e) is preferably the same or different and each is

-   (1) a halogen atom (particularly, a chlorine atom, a fluorine atom),    or-   (2) a alkyl group (particularly, a methyl group) optionally    substituted by the same or different 1 to 5 substituents    (particularly, a hydroxy group) selected from group C; more    preferably, a fluorine atom, a chlorine atom, a methyl group, a    hydroxymethyl group and the like.-   n

n is an integer of 0, or 1 to 3, preferably an integer of 0, or 1 to 2,particularly preferably 0.

As preferable embodiment of the compound represented by the formula [I],a compound represented by the following formula can be mentioned.

Here, as the compound represented by the formula [I], preferred is acompound represented by the formula [II], more preferred is a compoundrepresented by the formula [III] or a compound represented by theformula [VI].

As a compound represented by the formula [III], preferred is the formula[III-E], and as a compound represented by the formula [VI], preferred isa compound represented by the formula [VI-A].

As a compound represented by the formula [IV], preferred is a compoundrepresented by the formula [IV-D] or [IV-F].

As a compound represented by the formula [IV-D], preferred is a compoundwherein R^(a) is a hydrogen atom, R^(c) is a hydrogen atom, R^(d) is—CH₃, —CH₂—OH or —C(═O)—NH₂, and n=0.

As a compound represented by the formula [IV-F], preferred is a compoundwherein R^(a) is a hydrogen atom, R^(c) is a hydrogen atom, R^(d) is—CH₃, and n=0.

One example of preferable combination of each symbol in a compoundrepresented by the formula [III] is explained in the following.

In a preferable combination,

-   R^(a) is a hydrogen atom, a fluorine atom or a chlorine atom,    particularly a hydrogen atom,-   R^(b) is-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A,-   (4) a C₂₋₆ alkenyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (5) a C₂₋₆ alkynyl group optionally substituted by the same or    different 1 to 5 substituents selected from group C,-   (6) a cyano group,-   (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B,-   (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or    a C₁₋₆ alkyl group optionally substituted by the same or different 1    to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl    group optionally substituted by the same or different 1 to 5    substituents selected from group B, or-   (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    optionally substituted by the same or different 1 to 5 substituents    selected from group B,-   particularly,-   (1) a hydrogen atom,-   (2) a halogen atom (particularly, a fluorine atom, a chlorine atom,    a bromine atom),-   (3) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, an isobutyl group, an    isopentyl group, a neopentyl group, a 3,3-dimethylbutyl group)    optionally substituted by the same or different 1 to 5 substituents    selected from group A-   [particularly,-   (i) —C(═O)—OR^(A2) wherein R^(A2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (ii) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group,-   (iii) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (iv) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a 5 methyl group),-   (v) —NR^(A10)—C(═O)—R^(A11) wherein R^(A10) and R^(A11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), and-   (vi) —Si—(CH₂—CH₃)₃]-   (particularly, a hydroxy group, a methoxy group, a carboxy group, a    methoxycarbonyl group, a carbamoyl group, an acetylamino group, a    methylamino group, an N-acetyl-N-methylamino group, a triethylsilyl    group),-   (4) a C₂₋₆ alkenyl group (particularly, a 1-propenyl group, a    2-methyl-1-propenyl group),-   (5) a C₂₋₆ alkynyl group (particularly, an ethynyl group),-   (6) a cyano group,-   (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group),-   (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, a propyl group, a    butyl group) optionally substituted by the same or different 1 to 5    substituents selected from group B (particularly, a hydroxy group),-   (10) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group, an ethyl group, a propyl group,    an isopropyl group, a butyl group, an isobutyl group, a tert-butyl    group, a pentyl group, an isopentyl group, a neopentyl group, a    hexyl group) optionally substituted by the same or different 1 to 5    substituents selected from group B-   [particularly,-   (i) —C(═O)—OR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group, an ethyl group),-   (ii) —C(═O)—NR^(B3)R^(B4) wherein R^(B3) and R^(B4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group) optionally    substituted by the same or different 1 to 5 substituents selected    from group C (particularly, a hydroxy group, a carboxyl group),-   (iii) —OR^(B7) wherein R^(B7) is a hydrogen atom or a C₁₋₆ alkyl    group,-   (iv) —NR^(B8)R^(B9) wherein R^(B8) and R^(B9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group) optionally substituted by the same or    different 1 to 5 substituents selected from group C (particularly, a    carboxyl group),-   (v) —NR^(B10)—C(═O)—R^(B11) wherein R^(B10) and R^(B11) are the same    or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, an isopropyl group, a    tert-butyl group) optionally substituted by the same or different 1    to 5 substituents selected from group C (particularly, a hydroxy    group, a carboxyl group, a trifluoroacetyl group),-   (vi) —NR^(B12)—S(═O)₂—R^(B13) wherein R^(B12) and R^(B13) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), and-   (vii) —NR^(B14)—C(═O)—OR^(B15) wherein R^(B14) is a hydrogen atom or    a C₁₋₆ alkyl group (particularly, a methyl group, a tert-butyl    group), and R^(B15) is a C₁₋₆ alkyl group (particularly, a methyl    group, a tert-butyl group)]-   (particularly, a carboxyl group, a methoxycarbonyl group, an    ethoxycarbonyl group, a hydroxy group, a carbamoyl group, a    methylcarbamoyl group, a dimethylcarbamoyl group, an amino group, a    methylamino group, a dimethylamino group, a tert-butoxycarbonylamino    group, an acetylamino group, an N-tert-butoxycarbonyl-N-methylamino    group, an N-acetyl-N-methylamino group, an    N-hydroxyacetyl-N-methylamino group, an    N-acetyl-N-(2-hydroxyethyl)amino group, an    N-(2-hydroxyethyl)carbamoyl group, an    N-(2-hydroxyethyl)-N-methylcarbamoyl group, an    N,N-bis(2-hydroxyethyl)carbamoyl group, an    N-methyl-N-methanesulfonylamino group, an    N-acetyl-N-(2-carboxyethyl)amino group, an    N-carboxymethyl-N-methylamino group, an    N-carboxymethyl-N-methylcarbamoyl group, an    N-(2-carboxyethyl)-N-methylcarbamoyl group, a    3-(trifluoroacetyl)propionylamino group, an    N-(2,2-dimethylpropionyl)-N-methylamino group, an    N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino group, an    N-(2-hydroxy-2-methylpropionyl)-N-methylamino group),-   (11) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   (12) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group), or-   (13) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group),-   R^(c) is-   (1) a hydrogen atom,-   (2) a halogen atom (particularly, a fluorine atom, a chlorine atom),-   (3) a methyl group,-   (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atom or a methyl    group,-   (5) —OR^(c2) wherein R^(c2) is a hydrogen atom, a methyl group or an    ethyl group,-   (6) —NH₂, or-   (7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, an isopropyl group),    particularly a hydrogen atom,-   R^(m) is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E,-   (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    5 substituted by the same or different 1 to 5 substituents selected    from group F,-   (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic    heterocyclic group optionally substituted by the same or different 1    to 5 C₁₋₆ alkyl group (the monocyclic aromatic heterocyclic group    contains, besides carbon atom, 1 to 4 hetero atoms selected from a    nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7    ring-constituting atoms),-   (6) a C₃₋₁₀ cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (7) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F,-   more preferably,-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E′,-   (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F,-   particularly,-   (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, a butyl group, an    isobutyl group, a tert-butyl group, a neopentyl group) optionally    substituted by the same or different 1 to 5 substituents selected    from-   (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F,-   (ii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or    different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group, an ethyl group, an isopropyl group)    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (iii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F, and-   (iv) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the    same or different and each is a hydrogen atom or a C₁₋₆ alkyl group    (particularly, a methyl group) optionally substituted by the same or    different 1 to 5 substituents selected from group F,-   (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a    cyclopentyl group) optionally substituted by the same or different 1    to 5 substituents selected from group F (particularly, a hydroxy    group, a hydroxymethyl group, a carboxyl group), or-   (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, an adamantyl    group) optionally substituted by the same or different 1 to 5    substituents selected from group F,-   further particularly,-   (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl    group, a propyl group, an isopropyl group, a butyl group, an    isobutyl group, a tert-butyl group, a neopentyl group) optionally    substituted by the same or different 1 to 5 substituents selected    from-   (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F, and-   (ii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl    group (particularly, a methyl group) optionally substituted by the    same or different 1 to 5 substituents selected from group F,-   (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a    cyclopentyl group) optionally substituted by the same or different 1    to 5 substituents selected from group F (particularly, a hydroxy    group, a hydroxymethyl group, a carboxyl group), or-   (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, a 1-adamantyl    group) optionally substituted by the same or different 1 to 5    substituents selected from group F,-   particularly,

-   is a group represented by the following,

-   R^(e) is the same or different and each is a fluorine atom, a    chlorine atom, a methyl group, or a hydroxymethyl group,-   n is an integer of 0, or 1 to 2, particularly 0.

As specifically preferable compounds of the compound represented by theformula [I], the following compounds can be mentioned.

-   1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylic    acid dimethylamide (compound No. 153)-   1-[2-(5-hydroxy-5-trifluoromethyl-5H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one    (compound No. 430)-   4-hydroxymethyl-2-(1-ethyl-1H-pyrazol-4-yl)-9-trifluoromethyl-9H-fluoren-9-ol    (compound No. 629)-   2-[1-(2,2-dimethyl-propyl)-1H-pyrazol-4-yl]-4-hydroxymethyl-9-trifluoromethyl-9H-fluoren-9-ol    (compound No. 660)-   (−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic    acid amide (compound No. 630)-   2-[1-(2,2-dimethyl-propyl)-1H-pyrazol-4-yl]-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic    acid amide (compound No. 659)-   2-(1-cyclohexylmethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic    acid amide (compound No. 667)-   (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol    (compound No. 595)-   (+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic    acid (compound No. 538)-   (+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric    acid (compound No. 539)

In addition, in the compound represented by the formula [I], various“isomers” are present. When an asymmetric carbon atom is present at the9-position of the fluorene ring of the compound represented by theformula [I], enantiomers exist as a stereoisomer based thereon, and whenan asymmetric carbon atom is further present in a substituent,diastereomers exist.

Specifically, an optical active form of the compound represented by thefollowing chemical formulas and a mixture thereof are encompassed in thepresent invention.

In addition, an optically active form of the compound represented by thefollowing chemical formulas, which is a preferable embodiment of thecompound of the present invention, and a mixture thereof are encompassedin the present invention.

In addition, when E form and Z form exist as geometric isomers, and anaxial chirality is present, stereoisomers based on these exist. In somecases, tautomers may exist. Therefore, all of these isomers and mixturesthereof are encompassed in the present invention.

As a compound represented by the formula [III], preferred is a compoundrepresented by the formula [III-A].

As a compound represented by the formula [III-A], preferred is acompound wherein R^(m) is

-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group E′,-   (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally    substituted by the same or different 1 to 5 substituents selected    from group F,-   (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl    optionally substituted by the same or different 1 to 5 substituents    selected from group F,-   (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F, or-   (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or    different 1 to 5 substituents selected from group F.

In another embodiment, a specifically preferable compound of thecompound represented by the formula [I] is the following compound.

Particularly preferred is the following compound.

A pharmaceutically acceptable salt of the compound represented by theformula [I] (hereinafter to be also referred to as the compound of thepresent invention) may be any salt as long as it forms a nontoxic saltwith the compound of the present invention. Examples thereof includesalts with inorganic acids, salts with organic acids, salts withinorganic bases, salts with organic bases, salts with amino acids andthe like.

Examples of the salt with inorganic acid include a salt withhydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrobromic acid and the like.

Examples of the salt with organic acid include salts with oxalic acid,maleic acid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid,gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid and the like.

Examples of the salt with inorganic base include sodium salt, potassiumsalt, calcium salt, magnesium salt, ammonium salt and the like.

Examples of the salt with organic base include methylamine,diethylamine, trimethylamine, triethylamine, ethanolamine,diethanolamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline,cinchonine, meglumine and the like.

Examples of the salt with amino acid include salts with lysine,arginine, aspartic acid, glutamic acid and the like.

When a salt of the formula [I] is desired, each salt can be obtained byreacting a compound represented by the formula [I] with an inorganicbase, organic base, inorganic acid, organic acid or amino acid accordingto a known method.

The “solvate” is a compound represented by the formula [I] or apharmaceutically acceptable salt thereof wherein a molecule of thesolvent is coordinated, and also includes hydrates. As the solvate, apharmaceutically acceptable solvate is preferable and includes, forexample, hydrate, ethanolate, dimethylsulfoxidate and the like of thecompound represented by the formula [I] or a pharmaceutically acceptablesalt thereof. Specific examples thereof include hemihydrate,monohydrate, dihydrate and monoethanolate of the compound represented bythe formula [I], monohydrate of sodium salt, ⅔ ethanolate ofdihydrochloride, and the like of the compound represented by the formula[I].

The solvate can be obtained according to a method known per se.

In addition, the compound represented by the formula [I] may be labeledwith an isotope (e.g., 3H, ¹⁴C, ³⁵S etc.).

The deuterium derivative wherein ¹H of the compound represented by theformula [I] is substituted with ²H(D) is also encompassed in thecompound represented by the formula [I].

As the compound represented by the formula [I] or a pharmaceuticallyacceptable salt thereof or a solvate thereof, a compound represented bythe formula [I] or a pharmaceutically acceptable salt thereof or asolvate thereof, each of which is substantially purified, is preferable.More preferred is, a compound represented by the formula [I] or apharmaceutically acceptable salt thereof or a solvate thereof, each ofwhich is purified to a purity of not less than 80%.

In the present invention, a prodrug of the compound represented by theformula [I] can also be a useful medicament. The “prodrug” is aderivative of the compound of the present invention having a chemicallyor metabolically degradable group which, after administration to thebody, restores to the original compound by, for example, hydrolysis,solvolysis or decomposition under physiological conditions, and showsinherent efficacy. It is considered to include a noncovalent complex,and a salt. Prodrug is utilized for, for example, improvement ofabsorption on oral administration, or targeting to a target moiety.

Examples of the modified moiety include, in the compound of the presentinvention, a highly reactive functional group such as a hydroxyl group,a carboxyl group, an amino group and the like.

Specific examples of the hydroxyl-modifying group include an acetylgroup, a propionyl group, an isobutyryl group, a pivaloyl group, apalmitoyl group, a benzoyl group, a 4-methylbenzoyl group, adimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a sulfogroup, an alanyl group, a fumaryl group, a 3-carboxybenzoyl group, a2-carboxyethylcarbonyl group and the like. In addition, sodium salt of3-carboxybenzoyl group, 2-carboxyethylcarbonyl group and the like can bementioned.

Specific examples of the carboxyl-modifying group include a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, an isobutyl group, a tert-butyl group, a pivaloyloxymethyl group,a carboxymethyl group, a dimethylaminomethyl group, a 1-(acetyloxy)ethylgroup, a 1-(ethoxycarbonyloxy)ethyl group, a1-(isopropyloxycarbonyloxy)ethyl group, a1-(cyclohexyloxycarbonyloxy)ethyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a benzyl group, a phenylgroup, an o-tolyl group, a morpholinoethyl group, anN,N-diethylcarbamoylmethyl group, a phthalidyl group and the like.

Specific examples of the amino-modifying group include a tert-butylgroup, a docosanoyl group, a pivaloyloxymethyl group, an alanyl group, ahexylcarbamoyl group, a pentylcarbamoyl group, a3-methylthio-1-(acetylamino)propylcarbonyl group, a1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, atetrahydrofuranyl group, a pyrrolidylmethyl group and the like.

Examples of the “pharmaceutical composition” include oral preparationssuch as tablet, capsule, granule, powder, troche, syrup, emulsion,suspension and the like, and parenteral agents such as externalpreparation, suppository, injection, eye drop, nasal preparation,pulmonary preparation and the like.

The pharmaceutical composition of the present invention is producedaccording to a method known in the art of pharmaceutical preparations,by mixing a compound represented by the formula [I] or apharmaceutically acceptable salt thereof or a solvate thereof with asuitable amount of at least one kind of pharmaceutically acceptablecarrier and the like as appropriate. While the content of the compoundrepresented by the formula [I] or a pharmaceutically acceptable saltthereof, or a solvate thereof in the pharmaceutical composition variesdepending on the dosage form, dose and the like, it is, for example, 0.1to 100 wt % of the whole composition.

Examples of the “pharmaceutically acceptable carrier” include variousorganic or inorganic carrier substances conventionally used aspreparation materials, for example, excipient, disintegrant, binder,fluidizer, lubricant and the like for solid preparations, and solvent,solubilizing agent, suspending agent, isotonicity agent, bufferingagent, soothing agent and the like for liquid preparations. Wherenecessary, moreover, additives such as preservative, antioxidant,colorant, sweetening agent and the like are used.

Examples of the “excipient” include lactose, sucrose, D-mannitol,D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystallinecellulose, carmellose, carmellose calcium, sodium carboxymethyl starch,low-substituted hydroxypropylcellulose, gum arabic and the like.

Examples of the “disintegrant” include carmellose, carmellose calcium,carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium,crospovidone, low-substituted hydroxypropylcellulose,hydroxypropylmethylcellulose, crystalline cellulose and the like.

Examples of the “binder” include hydroxypropylcellulose,hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose,dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.

Examples of the “fluidizer” include light anhydrous silicic acid,magnesium stearate and the like.

Examples of the “lubricant” include magnesium stearate, calciumstearate, talc and the like.

Examples of the “solvent” include purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the “solubilizing agents” include propylene glycol,D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate,sodium citrate and the like.

Examples of the “suspending agent” include benzalkonium chloride,carmellose, hydroxypropylcellulose, propylene glycol, povidone,methylcellulose, glycerol monostearate and the like.

Examples of the “isotonicity agent” include glucose, D-sorbitol, sodiumchloride, D-mannitol and the like.

Examples of the “buffering agent” include sodium hydrogenphosphate,sodium acetate, sodium carbonate, sodium citrate and the like.

Examples of the “soothing agent” include benzyl alcohol and the like.

Examples of the “preservative” include ethyl parahydroxybenzoate,chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid andthe like.

Examples of the “antioxidant” include sodium sulfite, ascorbic acid andthe like.

Examples of the “colorant” include food colors (e.g., Food Color Red No.2 or 3, Food Color yellow No. 4 or 5 etc.), β-carotene and the like.

Examples of the “sweetening agent” include saccharin sodium, dipotassiumglycyrrhizinate, aspartame and the like.

The pharmaceutical composition of the present invention can beadministered orally or parenterally (e.g., topical, rectal, intravenousadministration etc.) to human as well as mammals other than human (e.g.,mouse, rat, hamster, guinea pig, rabbit, cat, dog, swine, bovine, horse,sheep, monkey etc.). The dose varies depending on the subject ofadministration, disease, symptom, dosage form, administration route andthe like. For example, the daily dose for oral administration to anadult patient (body weight: about 60 kg) is generally within the rangeof about 1 mg to 1 g, based on the compound of the present invention asthe active ingredient. This amount can be administered in one to severalportions.

The compound represented by the formula [I] or a pharmaceuticallyacceptable salt thereof, or a solvate thereof has inhibitory activityagainst pyruvate dehydrogenase kinase (PDHK, particularly PDHK2), andcan activate pyruvate dehydrogenase (PDH) effectively. Therefore, thecompound of the present invention or a pharmaceutically acceptable saltthereof, or a solvate thereof can be used as an active ingredient of anagent for the treatment or prophylaxis of diabetes (e.g., type 1diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolicsyndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrialdisease, mitochondrial encephalomyopathy or cancer. Furthermore, thecompound can be used as an active ingredient of an agent for thetreatment or prophylaxis of diabetic complications (e.g., neuropathy,retinopathy, nephropathy, cataract etc.), cerebral ischemia, cerebralapoplexy or pulmonary hypertension.

To “inhibit PDHK” means to specifically inhibit the function of PDHK andeliminate or attenuate the activity. To “inhibit PDHK”, human PDHK ispreferably inhibited. As a “PDHK inhibitor”, preferred is a “human PDHKinhibitor”.

To “inhibit PDHK2” means to specifically inhibit the function of PDHK2and eliminate or attenuate the activity. For example, it means tospecifically inhibit the function as PDHK2 based on the conditions inthe below-mentioned Experimental Example 1. To “inhibit PDHK2”, humanPDHK2 is preferably inhibited. As a “PDHK2 inhibitor”, preferred is a“human PDHK2 inhibitor”.

To “activate PDH” means to activate PDH in a target organ (e.g., liver,skeletal muscle, adipose tissue, heart, brain) and the like, cancer orthe like.

To “decrease blood glucose level” means to decrease the glucoseconcentration in blood (including in serum and plasma), preferably todecrease high blood glucose level, more preferably, to decrease theblood glucose level to normal level for human.

The above-mentioned compound represented by the formula [I] or apharmaceutically acceptable salt thereof, or a solvate thereof can beused in combination with one or a plurality of other medicaments(hereinafter to be also referred to as a concomitant drug) according toa method generally employed in the medical field (hereinafter to bereferred to as combined use).

The administration period of the above-mentioned compound represented bythe formula [I] or a pharmaceutically acceptable salt thereof, or asolvate thereof, and a concomitant drug is not limited, and they may beadministered to an administration subject as combination preparation, orthe both preparations may be administered simultaneously or at givenintervals. In addition, the pharmaceutical composition of the presentinvention and a concomitant drug may be used as a medicament in the formof a kit. The dose of the concomitant drug is similar to theclinically-employed dose and can be appropriately selected according tothe subject of administration, disease, symptom, dosage form,administration route, administration time, combination and the like. Theadministration form of the concomitant drug is not particularly limited,and it only needs to be combined with the compound of the presentinvention or a salt thereof, or a solvate thereof.

Examples of the concomitant drug include an agent for the treatmentand/or prophylaxis of diabetes and the like, and 1 to 3 agents therefromand the compound represented by the formula [I] or a pharmaceuticallyacceptable salt thereof, or a solvate thereof can be used incombination.

Examples of the “agent for the treatment and/or prophylaxis of diabetes”include insulin preparation, sulfonylurea hypoglycemic agent and thelike.

In the following, one example of the production method of the compoundto be used for the embodiment of the present invention is explained.However, the production method of the compound of the present inventionis not limited thereto.

Even if no directly corresponding disclosure is found in the followingProduction Methods, the steps may be modified for efficient productionof the compound, such as introduction of a protecting group into afunctional group with deprotection in a subsequent step, subjecting afunctional group as a precursor to each step, followed by conversion toa desired functional group at a suitable stage, changing the order ofProduction Methods and steps, and the like.

The treatment after reaction in each step may be conventional ones,where isolation and purification can be performed as necessary accordingto a method appropriately selected from conventional methods such ascrystallization, recrystallization, distillation, partitioning, silicagel chromatography, preparative HPLC and the like, or a combination ofthose methods.

Production Method 1 (Production Method of a Compound Represented by theFormula [I])

-   wherein each symbol is as defined above.    (Step 1)

Compound [Ia] is reacted with trimethyl(trifluoromethyl)silane in asolvent in the presence of a catalyst to allow trifluoromethylation togive trimethylsilyl ether of compound [1]. Then, the obtainedtrimethylsilyl ether is hydrolyzed to give compound [1] as a racemate.

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide, N,N-dimethylacetamide etc. and thelike. They can be used alone or two or more kinds thereof may be used ina mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the catalyst to be used for the trifluoromethylationreaction include alkali metal carbonates such as potassium carbonate andthe like; alkali metal acetates such as lithium acetate and the like;fluorides such as tetrabutylammonium fluoride etc., and the like.Preferred is potassium carbonate or lithium acetate.

The reaction temperature of the trifluoromethylation is generally about0 to 50° C., preferably about 0° C. to room temperature.

The reaction time of the trifluoromethylation is generally about 30 minto 1 day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generallyabout 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound[Ia].

The amount of the catalyst of the trifluoromethylation reaction to beused is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol,per 1 mol of compound [Ia].

Examples of the reagent to be used for the hydrolysis of trimethylsilylether include alkali metal fluorides such as cesium fluoride and thelike; ammonium fluoride salts such as tetrabutylammonium fluoride etc.,and the like.

When trimethylsilyl ether is hydrolyzed, the reaction temperature isgenerally about −10 to 50° C., preferably about 0° C. to roomtemperature.

When trimethylsilyl ether is hydrolyzed, the reaction time is generallyabout 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for the hydrolysis oftrimethylsilyl ether is generally about 1 to 5 mol, preferably about 1to 2 mol, per 1 mol of compound [Ia].

When optically active compound [I] is desired, the desired opticallyactive compound [I] can be obtained by separating racemate according topreferential crystallization method, diastereomer method, opticalresolution method using chiral stationary phase column and the like.

Production Method 2 (Production Method of a Compound Represented by theFormula [II] Wherein Y^(d) is a Single Bond (Compound [IIo]))

-   wherein-   “Hal¹” is a halogen atom, preferably a bromine atom, a chlorine atom    or an iodine atom;-   “Hal²” is a halogen atom, preferably a chlorine atom or a bromine    atom;-   “R^(Y1)” and “R^(Y2)” are the same or different and each is a    carboxyl-protecting group such as a alkyl group (e.g., a methyl    group, an ethyl group, t-butyl etc.), a benzyl group and the like;-   at least one of the substituents “R^(Z1)” to “R^(Z3)” of amine has    an asymmetric center and a single steric configuration (e.g.,    (R)-1-phenylethyl-1-yl, (S)-1-phenylethyl-1-yl,    (R)-1-(1-naphthyl)ethyl-1-yl, (S)-1-(1-naphthyl)ethyl-1-yl etc.),    and the rest is, for example, a hydrogen atom, alkyl groups such as    a methyl group, an ethyl group and the like, an optionally    substituted aralkyl group such as a benzyl group and the like, and    the like;-   “M” is a group including boron, zinc, tin or the like, for example,    boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like;-   the substituent “R^(X)” of the boron compound is, for example, a    hydrogen atom, an alkyl group such as a methyl group and the like,    or when it is “—B(OR^(X))₂”, two R^(X), oxygen atoms and a boron    atom bonded thereto in combination optionally form    4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl or the like;-   “R^(k0)” is a substituent capable of conversion to “R^(k)” (e.g.,    (cyclo)alkyl group etc. substituted by carboxylic acid, carboxamide,    alcohol etc.) by various functional group conversion reactions    (e.g., (cyclo)alkyl group etc. substituted by ester, ether etc.);-   “*” is an asymmetric center;-   a compound having “*” is an optically active form;-   a compound having “(*)” is a racemate or an optically active form;    and-   other symbols are as defined above.    (Step 10)

Compound [IIa] is reacted with compound [IIb] in a solvent in thepresence of a metal catalyst and a base to give compound [IIc].

Here, M of compound [IIb] is a group containing boron, zinc, tin or thelike. Examples thereof include boronic acid, dialkoxyboron,halogenozinc, trialkyltin and the like. Preferred are dialkoxyboron andboronic acid, and particularly preferred is4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbonsolvents such as toluene and the like; ether solvents such astetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amidesolvents such as dimethylformamide and the like; dimethyl sulfoxide;water and the like. They can be used alone or two or more kinds thereofmay be used in a mixture. Preferable solvent for this reaction is amixed solvent of toluene and water.

Examples of the metal catalyst to be used for the reaction include thosehaving palladium or nickel, and preferred are palladium, particularlypreferably palladium(II) acetate,dichlorobis(triphenylphosphine)palladium(II),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride,tetrakis(triphenylphosphine)palladium(0).

The amount of the metal catalyst to be used is generally about 0.001 to1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIa].

Examples of the base to be used for the reaction include alkali metalphosphates such as tripotassium phosphate and the like; alkali metalcarbonates such as sodium carbonate and the like; alkali metal acetatesuch as sodium acetate and the like; organic bases such as triethylamineand the like, preferably tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C.,preferably about 90 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about1-2 hr.

The amount of compound [IIb] to be used is generally about 1 to 5 mol,preferably about 1 to 2 mol, per 1 mol of compound [IIa].

The amount of the base to be used is generally about 1 to 5 mol,preferably about 1.5 to 3 mol, per 1 mol of compound [IIa].

(Step 11)

Compound [IId] can be obtained by subjecting compound [IIc] to esterhydrolysis in a solvent.

The ester hydrolysis may be performed under general conditions, forexample, under alkaline conditions or acidic conditions.

When the hydrolysis is performed under alkaline conditions, compound[IIc] is reacted, for example, in the presence of about 1 to 20 mol of abase (alkali metal hydroxide such as potassium hydroxide, sodiumhydroxide, lithium hydroxide etc., and the like) per 1 mol of compound[IIc] in, for example, water; alcohol solvents such as methanol, ethanoland the like; ether solvents such as tetrahydrofuran, dioxane etc., andthe like, or a mixed solvent of two or more kinds thereof generally atabout 0° C. to 100° C. for about 30 min to 1 day.

For reaction under acidic conditions, compound [IIc] is reacted in thepresence of, for example, about 0.1 to 100 mol of an acid (hydrochloricacid, sulfuric acid etc.) per 1 mol of compound [IIc] in, for example,water; carboxylic acid solvents such as acetic acid and the like; ethersolvents such as tetrahydrofuran, dioxane, etc., and the like, or amixed solvent of two or more kinds thereof generally at about 0° C. to100° C. for about 30 min to 2 days.

(Step 12)

Compound [IIe] can be obtained by cyclization reaction of compound [IId]in the presence of an acid without solvent or in a solvent.

Examples of the acid to be used for the reaction include phosphoruspentoxide, polyphosphoric acid and the like. The amount thereof to beused is generally about 1 mol to a large excess per 1 mol of compound[IId]. In addition, when a solvent is used, for example, methanesulfonicacid, sulfuric acid and the like can be mentioned. This reaction ispreferably performed without a solvent or in methanesulfonic acid as asolvent.

The reaction temperature is generally about 50 to 200° C., preferablyabout 80 to 180° C.

The reaction time is generally about 30 min to 1 day, preferably about1-3 hr.

(Step 13)

Compound [IIe] is reacted with trimethyl(trifluoromethyl)silane in asolvent in the presence of a catalyst to allow a trifluoromethylationreaction to give trimethylsilyl ether of compound [IIf], and theproduced trimethylsilyl ether is hydrolyzed to give compound [IIf] as aracemate.

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide, N,N-dimethylacetamide etc., and thelike. They can be used alone or two or more kinds thereof may be used ina mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the catalyst to be used for the trifluoromethylationreaction include alkali metal carbonates such as potassium carbonate andthe like; alkali metal acetates such as lithium acetate and the like;fluorides such as tetrabutylammonium fluoride etc., and the like.Preferred is potassium carbonate or lithium acetate.

The reaction temperature of the trifluoromethylation is generally about0 to 50° C., preferably about 0° C. to room temperature.

The reaction time of the trifluoromethylation is generally about 30 minto 1 day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generallyabout 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound[IIe].

The amount of the catalyst for the trifluoromethylation reaction to beused is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol,per 1 mol of compound [IIe].

Examples of the reagent to be used for hydrolysis of trimethylsilylether include alkali metal fluoride such as cesium fluoride and thelike; ammonium fluoride salt such as tetrabutylammonium fluoride etc.,and the like.

When trimethylsilyl ether is hydrolyzed, the reaction temperature isgenerally about −10 to 50° C., preferably about 0° C. to roomtemperature.

When trimethylsilyl ether is hydrolyzed, the reaction time is generallyabout 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for hydrolysis of trimethylsilylether is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1mol of compound [IIe].

(Step 14)

As a method for obtaining optically active compound [IIf], a methodcomprising steps 14a-14e from compound [IIe] or compound [IIf] can bementioned. By selecting an appropriate optically active amine for thismethod, (+) or (−) form of compound [IIf] can be produced.

(Step 14a)

Compound [IIg] wherein an acetic acid ester moiety is introduced can beobtained by trifluoromethylation reaction and hydrolysis oftrimethylsilyl ether in the same manner as in Step 13, followed byreaction with halogenated acetic acid ester.

Examples of the halogen atom of halogenated acetic acid ester to be usedinclude a chlorine atom, a bromine atom and an iodine atom. In addition,examples of the carboxyl-protecting group (R^(Y2)) include methyl,ethyl, t-butyl and the like. In this reaction, the halogenated aceticacid ester is preferably ethyl bromoacetate.

This acetic acid ester introduction reaction is performed by directlyadding halogenated acetic acid ester to a mixture of thetrifluoromethylation reaction product and the trimethylsilyl etherhydrolysis product.

The reaction temperature is generally about 0 to 50° C., preferablyabout 15 to 30° C.

The reaction time is generally about 30 min to 1 day, preferably about 1hr to 5 hr.

The amount of the halogenated acetic acid ester to be used is generallyabout 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound[IIe].

(Step 14a-2)

Compound [IIg] wherein an acetic acid ester moiety is introduced canalso be obtained by reacting isolated compound [IIf] with halogenatedacetic acid ester. The reaction for introducing acetic acid ester isperformed by reacting compound [IIf] with halogenated acetic acid esterin the presence of 1-5 equivalents (preferably, 2 equivalents) of a base(e.g., potassium carbonate etc.) at 0° C.-80° C. (preferably, roomtemperature) for 1-24 hr (preferably, overnight).

(Step 14b)

Compound [IIh] can be obtained by general ester hydrolysis of compound[IIg] in the same manner as in Step 11 in a solvent.

(Step 14c)

Compound [IIi], which is a salt of a single diastereomer, can beobtained as a solid by mixing compound [IIh] with an optically activeamine in a solvent.

Examples of the optically active amine to be used include(R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine,(R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine andthe like.

The amount of the optically active amine to be used is generally about0.1 to 1 mol, preferably about 0.4 to 0.6 mol, per 1 mol of compound[IIh].

Examples of the solvent to be used include ketone solvents such asmethyl ethyl ketone, methyl isobutyl ketone and the like; ester solventssuch as ethyl acetate and the like; ether solvents such as isopropylether etc., and the like. They can be used alone or two or more kindsthereof may be used in a mixture. Preferable solvent for this step ismethyl ethyl ketone, methyl isobutyl ketone.

The temperature for mixing is generally about 0 to 100° C., preferablyabout 20 to 70° C.

The time for the mixing is generally about 1 hr to 10 days, preferablyabout 1 to 5 days.

(Step 14d)

Compound [IIj] can be obtained by treating compound [IIi] with an acidicaqueous solution in a solvent to liberate carboxylic acid.

Examples of the solvent to be used include ester solvents such as ethylacetate and the like; ether solvents such as ethyl ether and the like;hydrocarbon solvents such as toluene etc., and the like. They can beused alone or two or more kinds thereof may be used in a mixture.Preferable solvent for this reaction is ethyl acetate.

Examples of the acidic aqueous solution to be used include hydrochloricacid, sulfuric acid and the like.

The treatment temperature is generally about 0 to 50° C., preferablyabout 0° C. to room temperature.

The treatment time is generally about 1 min to 2 hr.

The amount of the acidic aqueous solution to be used is generally about1 mol to large excess per 1 mol of compound [IIi].

(Step 14e)

Optically active compound [IIf] can be obtained by reacting compound[IIj] in a solvent.

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide and the like; alcohol solvents suchas t-butyl alcohol and the like; ether solvents such as dioxane and thelike; hydrocarbon solvents such as toluene and the like and the like.They can be used alone or two or more kinds thereof may be used in amixture. Preferable solvent for this reaction is a mixed solvent ofdimethylformamide and t-butyl alcohol.

The reagent to be used for the reaction is preferably diphenylphosphorylazide, and the base to be used for the reaction is a tertiary amine suchas triethylamine, N-ethyldiisopropylamine and the like.

The reaction temperature is generally about 0 to 150° C., preferablyabout 0 to 100° C.

The reaction time is generally about 30 min to 1 day, preferably about30 min to 5 hr.

The amount of diphenylphosphoryl azide to be used is generally about 1to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].

The amount of the base to be used is generally about 1 to 3 mol,preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].

(Step 15)

By treating racemic compound [IIf] using a chiral stationary phasecolumn and the like, a desired optically active compound [IIf] can beseparated from the other isomer.

(Step 16)

Compound [IIm] can be obtained by introducing R^(k0) into compound [IIk]in a solvent in the presence of a base such as potassium carbonate,cesium fluoride and the like.

For example, when R^(k0) is a (cyclo)alkyl group, compound [IIm] can beobtained by reacting compound [IIk] with (cyclo)alkyl halide such as(cyclo)alkyl iodide and (cyclo)alkyl bromide, (cyclo)alkyl sulfonic acidester such as (cyclo)alkyl tosylate, or an α,β-unsaturated carbonylcompound such as acrylic acid ester and the like in amide solvents suchas dimethylformamide, N,N-dimethylacetamide and the like oracetonitrile.

(Step 17)

Compound [IIn] can be obtained by reacting compound [IIf] in the form ofa racemate or an optically active form with compound [IIm] in a solventin the presence of a metal catalyst, a ligand and a base.

Boronic acid moiety of compound [IIm] is boronic acid per se, or boronicacid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbonsolvents such as toluene and the like; ether solvents such astetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amidesolvents such as dimethylformamide and the like; dimethyl sulfoxide;water and the like. They can be used alone or two or more kinds thereofmay be used in a mixture. Preferable solvent for this reaction is amixed solvent of toluene and water.

The metal catalyst to be used for the reaction is palladium such aspalladium(II)acetate, tris(dibenzylideneacetone)dipalladium(0),dichlorobis(triphenylphosphine)palladium(II) andtetrakis(triphenylphosphine)palladium(0), with preference given topalladium(II)acetate.

The amount of the metal catalyst to be used is generally about 0.001 to1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIf].

The ligand to be used for the reaction is phosphine such astriphenylphosphine, tributylphosphine,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like, withpreference given to 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.

Examples of the base to be used for the reaction include alkali metalphosphate such as tripotassium phosphate and the like; alkali metalcarbonate such as sodium carbonate and the like; alkali metalhydrogencarbonate such as sodium hydrogencarbonate and the like; alkalimetal acetate such as sodium acetate and the like; organic base such astriethylamine and the like, with preference given to tripotassiumphosphate.

The reaction temperature is generally about room temperature to 120° C.,preferably about 90 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about1-3 hr.

The amount of compound [IIm] to be used is generally about 1 to 5 mol,preferably about 1 to 2 mol, per 1 mol of compound [IIf].

The amount of the ligand to be used is generally about 1 to 5 mol,preferably about 1 to 3 mol, per 1 mol of the metal catalyst.

The amount of the base to be used is generally about 1 to 5 mol,preferably about 1 to 3 mol, per 1 mol of compound [IIf].

(Step 18)

The object compound [IIo] is obtained from compound [IIn] by generalfunctional group conversion or deprotection.

For example, when compound [IIo] contains a hydroxyl group, the compoundcan be converted by removal of the hydroxyl-protecting group orreduction of an ester thereof, which is a precursor.

For example, in the case of the former, when a hydroxyl group isprotected by a benzyl group, the compound can be converted by catalytichydrogenation reaction. When the hydroxyl group is protected by a silylgroup such as t-butyldimethylsilyl group and the like, the compound canbe converted by deprotection with tetrabutylammonium fluoride or thelike. When diol is protected by a ketal such as acetonide and the like,the compound can be converted by deprotection with acid such aspyridinium p-toluenesulfonate and the like. In the case of the latter,for example, the compound can be converted by a hydride reductionreaction using sodium borohydride, lithium aluminum hydride or the likein a single solvent such as tetrahydrofuran, tetrahydropyran, water andthe like or a mixture thereof. Alternatively, conversion is possible byconverting ester to carboxylic acid under general hydrolysis conditions,and reducing the acid with a reducing agent such as borane and the like.

Alternatively, compound [IIo] having a hydroxyl group can also beobtained by newly introducing a hydroxyl group. For example, ahydroxymethyl group can be introduced by reacting compound [IIn] havingan ester with paraformaldehyde in the presence of a base such astetrabutylammonium fluoride and the like. Alternatively, compound [IIo]having a hydroxyl group can also be obtained by introducing formyl groupby reacting compound [IIn] having an ester with formic acid ester suchas ethyl formate, t-butyl formate and the like in the presence of a basesuch as sodium hydride, potassium t-butoxide and the like, followed byhydride reduction.

When compound [IIo] has a carboxylic acid, compound [IIo] can beobtained by reacting an ester of compound [IIn] in the same manner as inStep 11 under general hydrolysis conditions. For example, when compound[IIn] is t-butyl ester, it can be converted to compound [IIo] underacidic conditions such as trifluoroacetic acid and the like.

When compound [IIo] has a tetrazole ring, the tetrazole ring can beintroduced by reacting a cyano group with trimethylsilylazide or thelike. A cyano group can be introduced by converting carboxylic acid andthe like to an amide and dehydrating the amide with trifluoroaceticanhydride and the like, or by the use of an alkylating agent having acyano group and the like.

When compound [IIo] has a sulfonamide group, a sulfonamide group can beintroduced by amidating an amino group with sulfonyl chloride or thelike. The amino group can be introduced by subjecting carboxylic acid toa rearrangement reaction, reacting alkyl halide with an amino sourcesuch as phthalimide potassium salt or the like.

The case wherein ring U is pyrazole in the step of obtaining compound[IIo] from compound [IIn] by a functional group conversion isexemplified below.

When Y^(d) is —C(═O)— bond, the compound can be synthesized by anamidation reaction of the corresponding carboxylic acid or an activatedderivative thereof with cyclic amine and the like, a reaction with acyclic organometallic reagent or the like.

For example, various derivatives can be synthesized by the followingstep.

wherein each symbol is as defined above.Production method 3 (production method of a compound represented by theformula [IV] wherein Y^(b) is a single bond (compound [IVn]))

wherein each symbol is as defined above.(Step 20)

Compound [IVc] can be obtained by reacting compound [IVa] with compound[IVb] in a solvent in the presence of a metal catalyst and a base.

Here, M in compound [IVb] is a group containing boron, zinc, tin or thelike and, for example, boronic acid, dialkoxyboron, halogenozinc,trialkyltin and the like can be mentioned. It is preferablydialkoxyboron or boronic acid, particularly preferably4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbonsolvents such as toluene and the like; ether solvents such astetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amidesolvents such as dimethylformamide and the like; dimethyl sulfoxide;water and the like. They can be used alone or two or more kinds thereofmay be used in a mixture. Preferable solvent for this reaction is amixed solvent of toluene and water.

A metal catalyst to be used for the reaction is one containing palladiumor nickel. Preferred is palladium, particularly preferablypalladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride ortetrakis(triphenylphosphine)palladium(0).

The amount of the metal catalyst to be used is generally about 0.001 to1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVa].

Examples of the base to be used for the reaction include alkali metalphosphates such as tripotassium phosphate and the like; alkali metalcarbonates such as sodium carbonate and the like; alkali metal acetatessuch as sodium acetate and the like; organic bases such as triethylamineand the like, with preference given to tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C.,preferably about 90 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about1-2 hr.

The amount of compound [IVb] to be used is generally about 1 to 5 mol,preferably about 1 to 2 mol, per 1 mol of compound [IVa].

The amount of the base to be used is generally about 1 to 5 mol,preferably about 1.5 to 3 mol, per 1 mol of compound [IVa].

(Step 21)

Compound [IVd] can be obtained by subjecting compound [IVc] to esterhydrolysis in a solvent.

Ester hydrolysis can be performed under general conditions and, forexample, under alkaline conditions or acidic conditions.

When it is performed under alkaline conditions, compound [IVc] isreacted, for example, in the presence of about 1 to 20 mol of a base(alkali metal hydroxide such as potassium hydroxide, sodium hydroxide,lithium hydroxide and the like etc.) per 1 mol of compound [IVc] in, forexample, water; alcohol solvents such as methanol, ethanol and the like;ether solvents such as tetrahydrofuran, dioxane, etc., and the like, ora mixed solvent of two or more kinds thereof generally at about 0° C. to100° C. for about 30 min to 1 day.

When it is performed under acidic conditions, compound [IVc] is reacted,for example, in the presence of about 0.1 to 100 mol of an acid(hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IVc] inthe presence of, for example, water; carboxylic acid solvents such asacetic acid and the like; ether solvents such as tetrahydrofuran,dioxane, etc., and the like, or a mixed solvent of two or more kindsthereof generally at about 0° C. to 100° C. for about 30 min to 2 days.

(Step 22)

Compound [IVe] can be obtained by reacting compound [IVd] to cyclizationin the presence of an acid with or without a solvent.

Examples of the acid to be used for the reaction include phosphoruspentoxide, polyphosphoric acid and the like. The amount thereof to beused is generally about 1 mol to a large excess, per 1 mol of compound[IVd]. When a solvent is used, for example, methanesulfonic acid,sulfuric acid and the like can be mentioned. This reaction is preferablyperformed without solvent or in methanesulfonic acid as a solvent.

The reaction temperature is generally about 50 to 200° C., preferablyabout 80 to 180° C.

The reaction time is generally about 30 min to 1 day, preferably about1-3 hr.

(Step 23)

Compound [IVe] is reacted with trimethyl(trifluoromethyl)silane in asolvent in the presence of a catalyst to perform a trifluoromethylationreaction to give a trimethylsilyl ether of compound [IVf], then theresulting trimethylsilyl ether is hydrolyzed to give compound [IVf] as aracemate.

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide, N,N-dimethylacetamide and the likeand the like. They can be used alone or two or more kinds thereof may beused in a mixture. Preferable solvent for this reaction isdimethylformamide.

Examples of the catalyst to be used for the trifluoromethylationreaction include alkali metal carbonates such as potassium carbonate andthe like; alkali metal acetates such as lithium acetate and the like;fluorides such as tetrabutylammonium fluoride and the like and the like,with preference given to potassium carbonate or lithium acetate.

The reaction temperature of trifluoromethylation is generally about 0 to50° C., preferably about 0° C. to room temperature.

The reaction time of trifluoromethylation is generally about 30 min to 1day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generallyabout 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound[IVe].

The amount of the catalyst to be used for the trifluoromethylationreaction is generally for about 0.01 to 1 mol, preferably about 0.05 to0.5 mol, per 1 mol of compound [IVe].

Examples of the reagent to be used for trimethylsilyl ether hydrolysisinclude alkali metal fluoride such as cesium fluoride and the like;ammonium fluoride salts such as tetrabutylammonium fluoride and the likeand the like.

The reaction temperature when trimethylsilyl ether is hydrolyzed isgenerally about −10 to 50° C., preferably about 0° C. to roomtemperature.

The reaction time when trimethylsilyl ether is hydrolyzed is generallyabout 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for trimethylsilyl ether hydrolysisis generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol ofcompound [IVe].

(Step 24)

Compound [IVg] can be obtained by reacting compound [IVf] in a solventin the presence of an oxidant.

Examples of the solvent to be used for the reaction include water,pyridine, t-butyl alcohol, acetone, acetic acid, sulfuric acid and thelike. They can be used alone or in a mixture with water. Preferablesolvent for this reaction is a mixed solvent of water and pyridine.

Examples of the oxidant to be used for the reaction includepermanganates such as potassium permanganate and the like, chromatessuch as sodium chromate and the like and the like, with preference givento potassium permanganate.

The reaction temperature is generally about 0 to 120° C., preferably 50to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about 1to 8 hr.

The amount of potassium permanganate to be used is generally about 2 to20 mol, preferably about 2 to 10 mol, per 1 mol of compound [IVf].

(Step 25)

As a method for obtaining optically active compound [IVg], a methodincludes Steps 25a-25b from a racemic compound [IVg]. In this method,(+) or (−) form of compound [IVg] can be produced by appropriatelyselecting an optically active amine.

(Step 25a)

Compound [IVh], which is a salt of single diastereomer, can be obtainedas a solid by mixing compound [IVg] with optically active amine in asolvent.

Examples of the optically active amine to be used include(R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine,(R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine andthe like.

The amount of the optically active amine to be used is generally about0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound[IVg].

Examples of the solvent to be used include ester solvents such as ethylacetate and the like; ether solvents such as isopropyl ether and thelike; ketone solvents such as methyl ethyl ketone, methyl isobutylketone and the like and the like. They can be used alone or two or morekinds thereof may be used in a mixture. Preferable solvent for this stepis ethyl acetate.

The temperature for mixing is generally about 0 to 100° C., preferablyabout 15 to 30° C.

The time for mixing is generally about 1 hr to 10 days, preferably about1 day to 3 days.

(Step 25b)

Optically active compound [IVg] can be obtained by treating compound[IVh] with acidic aqueous solution in a solvent, and liberatingcarboxylic acid.

Examples of the solvent to be used include ester solvents such as ethylacetate and the like; ether solvents such as ethyl ether and the like;hydrocarbon solvents such as toluene and the like and the like. They canbe used alone or two or more kinds thereof may be used in a mixture.Preferable solvent for this reaction is ethyl acetate.

Examples of the acidic aqueous solution to be used include hydrochloricacid, sulfuric acid and the like.

The treatment temperature is generally about 0 to 50° C., preferablyabout 0° C. to room temperature.

The treatment time is generally about 1 min to 2 hr.

The amount of the acidic aqueous solution to be used is generally about1 mol to large excess per 1 mol of compound [IVh].

(Step 26)

By treating racemic compound [IVg] using a chiral stationary phasecolumn and the like, a desired optically active compound [IVg] can beseparated from the other isomer.

The chiral stationary phase column to be used is, for example, Daicel,CHIRALCEL OD-RH.

Examples of the solvent for separation include a mixed solution ofacetonitrile and phosphate buffer wherein the composition ratio thereofis constant or varied.

For separation, a conventional high performance liquid chromatographyapparatus is used, which is performed while monitoring with a detectorsuch as ultraviolet absorption and the like.

(Step 27)

Compound [IVk] can be obtained by introducing R³ into compound [IVj] ina solvent in the presence of a base such as potassium carbonate and thelike.

For example, when R^(j) is a (cyclo)alkyl group, compound [IVk] can beobtained by reacting compound [IVj] with (cyclo)alkyl halide such as(cyclo)alkyl iodide, (cyclo)alkyl sulfonic acid ester such as(cyclo)alkyl tosylate or the like in amide solvents such asdimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.

(Step 28)

Compound [IVm] can be obtained by reacting compound [IVg] in the form ofa racemate or an optically active form with compound [IVk] in a solventin the presence of a metal catalyst, a ligand and a base.

Boronic acid moiety of compound [IVk] is boronic acid per se, or boronicacid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbonsolvents such as toluene and the like; ether solvents such astetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amidesolvents such as dimethylformamide and the like; dimethyl sulfoxide;water and the like. They can be used alone or two or more kinds thereofmay be used in a mixture. Preferable solvent for this reaction is amixed solvent of dioxane and water.

The metal catalyst to be used for the reaction is palladium, forexample, palladium(II)acetate,dichlorobis(triphenylphosphine)palladium(II),tetrakis(triphenylphosphine)palladium(0), with preference given topalladium(II)acetate.

The amount of the metal catalyst to be used is generally for about 0.001to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVg].

The ligand to be used for the reaction is phosphine such astriphenylphosphine, tributylphosphine,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like. Preferredis 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.

Examples of the base to be used for the reaction include alkali metalphosphates such as tripotassium phosphate and the like; alkali metalcarbonates such as sodium carbonate and the like; alkali metal acetatesuch as sodium acetate and the like, with preference given totripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C.,preferably about 90 to 110°.

The reaction time is generally about 30 min to 1 day, preferably about1-3 hr.

The amount of compound [IVk] to be used is generally about 1 to 5 mol,preferably about 1 to 2 mol, per 1 mol of compound [IVg].

The amount of the ligand to be used is generally about 1 to 5 mol,preferably about 1 to 3 mol, per 1 mol of the metal catalyst.

The amount of the base to be used is generally about 1 to 5 mol,preferably about 1 to 3 mol, per 1 mol of compound [IVg].

(Step 29)

The object compound [IVn] is obtained from compound [IVm] by generalfunctional group conversion or deprotection.

For example, when compound [IVn] contains carboxamide, the compound canbe obtained by reacting carboxylic acid with amine to allow amidationwith, for example, a condensation agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the likein the presence of 1-hydroxybenzotriazole hydrate in a solvent such asdimethylformamide, chloroform and the like. In this case, carboxylicacid may be converted in advance to acid chloride, mixed acid anhydrideor the like, and reacted with amine to allow amidation, whereby compound[IVn] containing carboxamide can be obtained.

When compound [IVn] has an ester, a general esterification reaction withalcohol needs to be performed. For example, carboxylic acid may beconverted in advance to an acid chloride, and reacted with alcohol inthe presence of a base such as pyridine and the like without solvent orin chloroform, whereby compound [IVn] having an ester can be obtained.Compound [IVn] having an ester can also be obtained by reactingcarboxylic acid with alkyl halide in the presence of a base such aspotassium carbonate in, for example, dimethylformamide.

When compound [IVn] contains a hydroxyl group, it can be obtained byreduction of carboxylic acid or a reaction with an organometallicreagent. In the case of the former, for example, compound [IVn]containing a hydroxyl group can be obtained by performing a hydridereduction reaction using borane, lithium aluminum hydride and the likein a single or mixed solvent of ethyl ether, tetrahydrofuran,tetrahydropyran and the like.

When Y^(b) is an amine bond (—NR^(b16)—), compound [IVn] wherein Y^(b)is an amine bond can be synthesized by subjecting compound [IVg] to acondensation reaction with amine compound or the like in the presence ofa catalyst such as palladium and the like.

When Y^(b) is alkanediyl, compound [IVn] wherein Y^(b) is alkanediyl canbe synthesized by subjecting compound [IVg] to a condensation reactionwith an organic zinc compound and the like in the presence of a catalystsuch as palladium and the like.

When Y^(b) is alkenediyl, compound [IVn] wherein Y^(b) is alkenediyl canbe synthesized by subjecting compound [IVg] to a condensation reactionwith an alkenylboron compound and the like in the presence of a catalystsuch as palladium and the like.

Production method 4 (production method of a compound represented by theformula [IV] wherein Y^(b) is —C(═O)— bond (compound [IVz]))

wherein

-   “R^(Y3)” and “R^(Y4)” are the same or different and each is a    carboxyl-protecting group such as a C₁₋₄ alkyl group (e.g., a methyl    group, an ethyl group, a t-butyl group etc.), a benzyl group and the    like;-   “R^(j0)” is a substituent (e.g., a carboxyl group etc.) that can be    converted to “R^(j)” (e.g., a carbamoyl group etc.) by various    functional group conversion reactions, and    other symbols are as defined above.    (Step 30)

Compound [IVp] can be obtained by reacting compound [IVo] with compound[IVb] in a solvent, in the presence of a metal catalyst and a base.

Here, M of compound [IVb] is a group containing boron, zinc, tin or thelike. Examples thereof include boronic acid, dialkoxyboron,halogenozinc, trialkyltin and the like. Preferred are dialkoxyboron andboronic acid, and particularly preferred is4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbonsolvents such as toluene and the like; ether solvents such astetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amidesolvents such as dimethylformamide and the like; dimethyl sulfoxide;water and the like. They can be used alone or two or more kinds thereofmay be used in a mixture. Preferable solvent for this reaction is amixed solvent of toluene and water.

Examples of the metal catalyst to be used for the reaction include thosehaving palladium or nickel, and preferred are palladium, andparticularly preferred are palladium(II)acetate,dichlorobis(triphenylphosphine)palladium(II),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride,tetrakis(triphenylphosphine)palladium(0).

The amount of the metal catalyst to be used is generally about 0.001 to1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVo].

Examples of the base to be used for the reaction include alkali metalphosphates such as tripotassium phosphate and the like; alkali metalcarbonates such as sodium carbonate and the like; alkali metal acetatessuch as sodium acetate and the like; organic bases such as triethylamineand the like, with preference given to tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C.,preferably about 90 to 110°.

The reaction time is generally about 30 min to 1 day, preferably about1-2 hr.

The amount of compound [IVb] to be used is generally about 1 to 5 mol,preferably about 1 to 2 mol, per 1 mol of compound [IVo].

The amount of the base to be used is generally about 1 to 5 mol,preferably about 1.5 to 3 mol, per 1 mol of compound [IVo].

(Step 31)

Compound [IVq] can be obtained by subjecting compound [IVp] to esterhydrolysis in a solvent.

The ester hydrolysis may be performed under general conditions, forexample, under alkaline conditions or acidic conditions.

When the hydrolysis is performed under alkaline conditions, compound[IVp] is reacted, for example, in the presence of about 1 to 20 mol of abase (alkali metal hydroxide such as potassium hydroxide, sodiumhydroxide, lithium hydroxide etc., and the like) per 1 mol of compound[IVp] in, for example, water; alcohol solvents such as methanol, ethanoland the like; ether solvents such as tetrahydrofuran, dioxane etc., andthe like, or a mixed solvent of two or more kinds thereof generally atabout 0° C. to 100° C. for about 30 min to 1 day.

For reaction under acidic conditions, compound [IVp] is reacted in thepresence of, for example, about 0.1 to 100 mol of an acid (hydrochloricacid, sulfuric acid etc.) per 1 mol of compound [IVp] in, for example,water; carboxylic acid solvents such as acetic acid and the like; ethersolvents such as tetrahydrofuran, dioxane, etc., and the like, or amixed solvent of two or more kinds thereof generally at about 0° C. to100° C. for about 30 min to 2 days.

(Step 32)

Compound [IVr] can be obtained by cyclization reaction of compound [IVq]in the presence of an acid without solvent or in a solvent.

Examples of the acid to be used for the reaction include phosphoruspentoxide, polyphosphoric acid and the like. The amount thereof to beused is generally about 1 mol to a large excess per 1 mol of compound[IVq]. In addition, when a solvent is used, for example, methanesulfonicacid, sulfuric acid and the like can be mentioned. This reaction ispreferably performed without a solvent or in methanesulfonic acid as asolvent.

The reaction temperature is generally about 50 to 200° C., preferablyabout 80 to 180° C.

The reaction time is generally about 30 min to 1 day, preferably about1-3 hr.

(Step 33)

Compound [IVs] can be obtained by esterification reaction of compound[IVr] with alkyl halide in a solvent in the presence of a base.

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide, N,N-dimethylacetamide and the like;dimethyl sulfoxide; water and the like. Preferable solvent for thisreaction is dimethylformamide.

Examples of the base to be used for the reaction include alkali metalcarbonates such as potassium carbonate and the like, alkali metalhydrides such as sodium hydride and the like; alkali metal hydroxidessuch as sodium hydroxide and the like, and the like; with preferencegiven to potassium carbonate.

Examples of the halogen of the alkyl halide to be used for the reactioninclude iodine, bromine and the like, and examples of the alkyl includemethyl, ethyl and the like. Preferred for this step is methyl iodide.

The reaction temperature is generally about 0 to 100° C., preferablyabout 0 to 80° C.

The reaction time is generally about 10 min to 1 day, preferably about30 min to 12 hr.

The amount of the base to be used is generally about 1 to 5 mol,preferably about 1 to 3 mol, per 1 mol of compound [IVr].

The amount of the alkyl halide to be used is generally about 1 to 5 mol,preferably about 1 to 3 mol, per 1 mol of compound [IVr].

(Step 34)

Compound [IVs] is reacted with trimethyl(trifluoromethyl)silane in asolvent in the presence of a catalyst to perform a trifluoromethylationreaction to give a trimethylsilyl ether of compound [IVt], then theresulting trimethylsilyl ether is hydrolyzed to give compound [IVt] as aracemate.

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide, N,N-dimethylacetamide and the like,and the like. They can be used alone or two or more kinds thereof may beused in a mixture. Preferable solvent for this reaction isdimethylformamide.

Examples of the catalyst to be used for the trifluoromethylationreaction include alkali metal carbonates such as potassium carbonate andthe like; alkali metal acetates such as lithium acetate and the like;fluorides such as tetrabutylammonium fluoride and the like; and thelike, with preference given to potassium carbonate and lithium acetate.

The reaction temperature of trifluoromethylation is generally about 0 to50° C., preferably about 0° C. to room temperature.

The reaction time of trifluoromethylation is generally about 30 min to 1day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generallyabout 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound[IVs].

The amount of the catalyst to be used for the trifluoromethylationreaction is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5mol, per 1 mol of compound [IVs].

Examples of the reagent to be used for the trimethylsilyl etherhydrolysis include alkali metal fluoride such as cesium fluoride and thelike; ammonium fluoride salts such as tetrabutylammonium fluoride andthe like; and the like.

The reaction temperature when trimethylsilyl ether is hydrolyzed isgenerally about −10 to 50° C., preferably about 0° C. to roomtemperature.

The reaction time when trimethylsilyl ether is hydrolyzed is generallyabout 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for trimethylsilyl ether hydrolysisis generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol ofcompound [IVs].

(Step 35)

Compound [IVu] can be obtained by subjecting compound [IVt] to esterhydrolysis in a solvent under alkaline conditions.

Examples of the solvent to be used for the reaction include water;alcohol solvents such as methanol, ethanol and the like; ether solventssuch as tetrahydrofuran, dioxane and the like; and the like. They can beused alone or two or more kinds thereof may be used in a mixture.Preferable solvents for this reaction is a mixed solvent of water,methanol and tetrahydrofuran.

Examples of the alkali to be used for the reaction include alkali metalhydroxide such as potassium hydroxide, sodium hydroxide, lithiumhydroxide and the like, and the like, with preference given to sodiumhydroxide.

The reaction temperature is generally about 0 to 120° C., preferablyabout 0 to 90° C.

The reaction time is generally about 10 min to 1 day, preferably about30 min to 12 hr.

The amount of the alkali to be used is generally about 1 mol to largeexcess, preferably about 1 to 10 mol, per 1 mol of compound [IVt].

(Step 36)

As a method for obtaining optically active compound [IVu], a methodincludes Steps 36a-36b from a racemic compound [IVu]. In this method,(+) or (−) form of compound [IVu] can be produced by appropriatelyselecting an optically active amine.

(Step 36a)

Compound [IVv], which is a salt of single diastereomer, can be obtainedas a solid by mixing compound [IVu] with an optically active amine in asolvent.

Examples of the optically active amine to be used include(R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine,(R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine andthe like.

The amount of the optically active amine to be used is generally about0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound[IVu].

Examples of the solvent to be used include ester solvents such as ethylacetate and the like; ether solvents such as ethyl ether and the like;and the like. They can be used alone or two or more kinds thereof may beused in a mixture. Preferable solvent for this step is ethyl acetate.

The temperature for mixing is generally about 0 to 100° C., preferablyabout 15 to 80° C.

The time for mixing is generally about 1 hr to 10 days, preferably about1 to 12 hr.

(Step 36b)

Optically active compound [IVu] can be obtained by treating compound[IVv] with acidic aqueous solution in a solvent, and liberatingcarboxylic acid.

Examples of the solvent to be used include ester solvents such as ethylacetate and the like; ether solvents such as ethyl ether and the like;hydrocarbon solvents such as toluene and the like and the like. They canbe used alone or two or more kinds thereof may be used in a mixture.Preferable solvent for this reaction is ethyl acetate.

Examples of the acidic aqueous solution to be used include hydrochloricacid, sulfuric acid and the like.

The treatment temperature is generally about 0 to 50° C., preferablyabout 0° C. to room temperature.

The treatment time is generally about 1 min to 2 hr.

The amount of the acidic aqueous solution to be used is generally about1 mol to large excess per 1 mol of compound [IVv].

(Step 37)

By treating racemic compound [IVu] using a chiral stationary phasecolumn and the like, a desired optically active compound [IVu] can beseparated from the other isomer.

The chiral stationary phase column to be used is, for example, Daicel,CHIRALCEL OD-RH.

Examples of the solvent for separation include a mixed solution ofacetonitrile and phosphate buffer wherein the composition ratio thereofis constant or varied.

For separation, a conventional high performance liquid chromatographyapparatus is used, which is performed while monitoring with a detectorsuch as ultraviolet absorption and the like.

(Step 38)

Compound [IVy] can be obtained by converting a precursor in R^(j0) ofcompound [IVx] to a functional group in R^(j) of compound [IVy].

For example, when R^(j) contains amide, compound [IVy] having amide inR^(j) can be obtained by amidation reaction of compound [IVx] havingcarboxylic acid for R^(j0) with amine in the presence of a condensationagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and the like and 1-hydroxybenzotriazole hydrate in asolvent such as dimethylformamide, chloroform and the like.

When a functional group influenced by conversion of a precursor inR^(j0) of compound [IVx] to a functional group in R^(j) of compound[IVy] is present in other part of compound [IVx], a protecting group maybe introduced as appropriate. For example, when an amino group ispresent in other part during production of compound [IVy] having amidein R^(j) by amidation of compound [IVx] having carboxylic acid forR^(j0), a protecting group such as t-butyloxycarbonyl group,benzyloxycarbonyl group and the like is introduced into the amino groupby a conventional method, a desired amidation reaction is performed, andthen deprotection is performed by a general method.

(Step 39)

Compound [IVz] can be obtained by reacting compound [IVu], which is aracemate or an optically active form, with compound [IVy].

When compound [IVy] is cyclic amine, compound [IVz] can be obtained bygeneral amidation reaction. For example, compound [IVu] and compound[IVy] are reacted in a solvent in the presence of a condensation agent.Examples of the condensation agent include1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in thecopresence of 1-hydroxybenzotriazole hydrate and the like, and examplesof the solvent include dimethylformamide, chloroform and the like.

Alternatively, compound [IVu], which is a racemate or an opticallyactive form, may be converted in advance to acid chloride, mixed acidanhydride or the like and reacted with compound [IVy], whereby compound[IVz] can be obtained.

In addition, compound [IVz] is obtained by reacting compound [IVy] withan organic base such as LDA and the like, and reacting the resultantwith compound [IVu] or, for example, an amide compound thereof withN,O-dimethylhydroxyamine or the like.

When Y^(b) is an ether bond etc., compound [IVz] wherein Y^(b) is anether bond etc. can be synthesized by subjecting the correspondingphenol compound to reactions such as Mitsunobu reaction, alkylationreaction with alkyl halide or alkyl sulfonate, and the like.

For example, various derivatives can be synthesized by the followingsteps.

wherein

-   “Po” is a hydroxyl-protecting group (e.g., a methyl group etc.); and    other symbols are as defined above.    Production method 5 (production method of a compound represented by    the formula [I] wherein Xd is a nitrogen atom (compound [V]))

wherein

-   “R^(b00)” is a substituent (e.g., a hydroxy group etc.) that can be    converted to “R^(b0)” (e.g., a methoxy group etc.) by various    functional group conversion reactions;-   “R^(b0)” is a substituent (e.g., a methoxy group etc.) that can be    converted to “R^(b)” (e.g., carboxamide, an alkoxy group substituted    by lactam and the like, an alkyl group etc.) by various functional    group conversion reactions; and    other symbols are as defined above.    (Step 41)

When a functional group influenced by the reaction in the next Step 42is present in compound [Va], a protecting group may be introduced intothe functional group as appropriate to give compound [Vb].

For example, when the functional group influenced by the reaction is ahydroxyl group, compound [Va] is subjected to alkylation reaction withan alkylating agent in a solvent in the presence of a base to givecompound [Vb].

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide and the like; ether solvents such astetrahydrofuran and the like; dimethylsulfoxide and the like. They canbe used alone or two or more kinds thereof may be used in a mixture.Preferable solvent for this reaction is dimethylformamide.

Examples of the alkylating agent to be used for the reaction includealkyl halide such as methyl iodide and the like; alkyl sulfonates suchas ethyl tosylate and the like; sulfuric acid esters such as methylsulfate and the like; and the like, with preference given to methyliodide.

Examples of the base to be used for the reaction include alkali metalcarbonates such as potassium carbonate and the like; alkali metalhydrides such as sodium hydride and the like; alkali metal hydroxidessuch as sodium hydroxide and the like; and the like, with preferencegiven to potassium carbonate.

The reaction temperature is generally about 0 to 120° C., preferablyabout 0 to 80° C.

The reaction time is generally about 30 min to 1 day, preferably about 1hr to 1 day.

The amount of the alkylating agent to be used is generally about 1 to 3mol, preferably about 1 to 2 mol, per 1 mol of compound [Va].

The amount of the base to be used is generally about 1 to 10 mol,preferably about 1 to 5 mol, per 1 mol of compound [Va].

(Step 42)

Compound [Vd] can be obtained by reacting compound [Vb] with compound[Vc] in a solvent in the presence of a metal catalyst and a base.

The boronic acid moiety of compound [Vc] is boronic acid per se, orboronic acid ester, preferably boronic acid per se.

Examples of the solvent to be used for the reaction include hydrocarbonsolvents such as toluene and the like; ether solvents such astetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amidesolvents such as dimethylformamide and the like; dimethyl sulfoxide;water and the like. They can be used alone or two or more kinds thereofmay be used in a mixture. Preferable solvent for this reaction is amixed solvent of toluene and water.

Examples of the metal catalyst to be used for the reaction include onecontaining palladium. Particularly preferred is1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride.

The amount of the metal catalyst to be used is generally about 0.001 to1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [Vb].

Examples of the base to be used for the reaction include alkali metalphosphates such as tripotassium phosphate and the like; alkali metalcarbonates such as sodium carbonate and the like; alkali metal acetatessuch as sodium acetate and the like, with preference given totripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C.,preferably about 70 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about1-3 hr.

The amount of compound [Vc] to be used is generally about 1 to 5 mol,preferably about 1 to 2 mol, per 1 mol of compound [Vb].

The amount of the base to be used is generally about 1 to 5 mol,preferably about 1.5 to 3 mol, per 1 mol of compound [Vb].

(Step 43)

Compound [Ve] can be obtained by cyclization reaction of compound [Vd]in a solvent in the presence of a base.

Examples of the solvent to be used for the reaction include hydrocarbonsolvents such as n-hexane and the like; ether solvents such astetrahydrofuran and the like; amide solvents such as N-methylpyrrolidoneand the like; and the like. They can be used alone or two or more kindsthereof may be used in a mixture. Preferable solvent for this reactionis tetrahydrofuran.

Examples of the base to be used for the reaction include amide basessuch as lithium N,N-diisopropylamide, lithium hexamethyldisilazide andthe like; organometalllics such as butyllithium and the like; and thelike, with preference given to lithium N,N-diisopropylamide.

The reaction temperature is generally about −78 to 100° C., preferablyabout −10 to 50° C.

The reaction time is generally about 10 min to 1 day, preferably about10 min to 3 hr.

The amount of the base to be used is generally about 1 to 10 mol,preferably about 1 to 3 mol, per 1 mol of compound [Vd].

(Step 44)

Compound [Vf] is obtained from compound [Ve] by general functional groupconversion or deprotection.

For example, when R^(b) is a (substituted) alkoxy group and R^(b00) ofcompound [Va] is a hydroxyl group which is subjected to alkyl groupprotection in the earlier Step 41, compound [Vf] wherein R^(b) is a(substituted) alkoxy group can be obtained by deprotection to regeneratethe hydroxyl group according to a conventional method, for example, byfusing compound [Ve] and pyridinium chloride and the like and,alkylation by, for example, Mitsunobu reaction and the like.

When R^(b) is a (substituted) alkyl group and R^(b00) of compound [Va]is a hydroxyl group which is subjected to alkyl group protection in theearlier Step 41, compound [Vf] wherein R^(b) is a (substituted) alkylgroup can be obtained by deprotection according to a conventional methodto regenerate the hydroxyl group, conversion totrifluoromethanesulfonate, a reaction of the trifluoromethanesulfonatecompound with a terminal acetylene compound or an alkenyl metal compoundsuch as an alkenylboron compound and the like in the presence of a metalcatalyst such as palladium and the like, and a hydrogenaion reaction.

(Step 45)

Compound [V] can be obtained as a racemate by reacting compound [Vf]with trimethyl(trifluoromethyl)silane in a solvent in the presence of acatalyst to cause trifluoromethylation reaction, whereby atrimethylsilyl ether of compound [V] is obtained, then hydrolyzing theresulting trimethylsilyl ether.

Examples of the solvent to be used for the reaction include amidesolvents such as dimethylformamide, N,N-dimethylacetamide and the like,and the like. They can be used alone or two or more kinds thereof may beused in a mixture. Preferable solvent for this reaction isdimethylformamide.

Examples of the catalyst to be used for the trifluoromethylationreaction include alkali metal carbonates such as potassium carbonate andthe like; alkali metal acetates such as lithium acetate and the like;fluorides such as tetrabutylammonium fluoride and the like; and thelike, with preference given to potassium carbonate and lithium acetate.

The reaction temperature of trifluoromethylation is generally about 0 to50° C., preferably about 0° C. to room temperature.

The reaction time of trifluoromethylation is generally about 30 min to 1day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generallyabout 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound[Vf].

The amount of the catalyst to be used for the trifluoromethylationreaction is generally for about 0.01 to 1 mol, preferably about 0.05 to0.5 mol, per 1 mol of compound [Vf].

Examples of the reagent to be used for the trimethylsilyl etherhydrolysis include alkali metal fluorides such as cesium fluoride andthe like; ammonium fluoride salts such as tetrabutylammonium fluorideand the like; and the like.

The reaction temperature when trimethylsilyl ether is hydrolyzed isgenerally about −10 to 50° C., preferably about 0° C. to roomtemperature.

The reaction time when trimethylsilyl ether is hydrolyzed is generallyabout 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for trimethylsilyl ether hydrolysisis generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol ofcompound [Vf].

As for compound [V], a desired optically active compound [V] can beseparated from the other isomer by a preferential crystallizationmethod, a diastereomer method, an optical resolution method using achiral stationary phase column, or the like.

Examples

The production of the compound of the present invention is specificallyexplained by Examples. However, the present invention is not limited bythese Examples.

The room temperature in the Examples means 1-40° C.

(Derivatization Method A for Determination of Optical Purity)

A solid (0.002-0.003 g) to be analyzed is shaken with ethyl acetate (0.1ml) and 1N hydrochloric acid (0.1 ml), the mixture was stood still toseparate layers. The upper layer (0.010 ml) was added to the followingpreparation solution (0.1 ml), and the mixture was shaken at 50° C. for30 min. The obtained mixture was analyzed by HPLC.

(Preparation Solution)

Dimethylformamide was added to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.191 g)and 1-hydroxybenzotriazole hydrate (0.153 g) to a total amount of 10 ml.(S)-(−)-1-(1-Naphthyl)-ethylamine (0.258 ml) was added to the mixture togive the title preparation solution.

(10 mM Phosphate Buffer (pH 2.0))

Potassium dihydrogen phosphate (4.08 g) was dissolved in water (3000 mL)and adjusted to pH 2.0 with phosphoric acid to give the title buffer.

HPLC Analysis Conditions

Analysis Condition 1

-   instrument: HPLC system SHIMADZU Corporation high-speed liquid    chromatography Prominence-   column: Daicel CHIRALCEL OD-RH 4.6 mmφ×150 mm-   column temperature: 40° C.-   mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0),    (SOLUTION B) acetonitrile-   the composition (SOLUTION A:SOLUTION B) of the mobile phase was    changed linearly from 50:50 to 20:80 over 20 min, thereafter, kept    constant at 20:80 for 5 min.-   flow rate: 0.5 ml/min-   detection: UV (220 nm)    Analysis Condition 2-   instrument: HPLC system SHIMADZU Corporation high-speed liquid    chromatography Prominence-   column: Daicel CHIRALCEL OD-RH 4.6 mmφ×150 mm-   column temperature: 40° C.-   mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0),    (SOLUTION B) acetonitrile-   the composition (SOLUTION A:SOLUTION B) of the mobile phase was    changed linearly from 70:30 to 40:60 over 20 min, thereafter, kept    constant at 40:60 for 5 min.-   flow rate: 0.5 ml/min-   detection: UV (220 nm)    Analysis Condition 3-   instrument: HPLC system SHIMADZU Corporation high-speed liquid    chromatography Prominence-   column: Daicel CHIRALCEL OJ-RH 4.6 mmφ×150 mm-   column temperature: 40° C.-   mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0),    (SOLUTION B) acetonitrile-   the composition (SOLUTION A:SOLUTION B) of the mobile phase was kept    constant at 70:30 for 25 min, thereafter, at 40:60 for 10 min.-   flow rate: 0.5 ml/min-   detection: UV (294 nm)    Analysis Condition 4-   instrument: HPLC system SHIMADZU Corporation high-speed liquid    chromatography Prominence-   column: Daicel CHIRALPAK AD-RH 4.6 mmφ×150 mm-   column temperature: 40° C.-   mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0),    (SOLUTION B) acetonitrile-   the composition (SOLUTION A:SOLUTION B) of the mobile phase was    changed linearly from 70:30 to 50:50 over 20 min, thereafter, kept    constant at 50:50 for 5 min.-   flow rate: 0.5 ml/min-   detection: UV (220 nm)

Example 1 Synthesis of(+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (compound No.526)

Step 1

2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid ethyl ester

To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g),ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g),toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g),and purged with argon. To this mixture was addeddichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixturewas stirred in an oil bath at 110° C. for 3 hr. The oil bath wasremoved, and water (125 ml) was added to the reaction mixture. Themixture was stirred at room temperature for 1 hr, and filtered throughcelite. The filtrate was partitioned in a separatory funnel. The aqueouslayer was extracted with toluene, and the organic layers were combined.The organic layer was washed twice with water (125 ml), dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedunder reduced pressure to give the title compound (41.8 g). The obtainedsolid was directly used for the next reaction without furtherpurification.

¹H-NMR (CDCl₃) δ: 8.06-8.02 (1H, m), 7.60-7.54 (1H, m), 7.52-7.45 (1H,m), 7.27-7.16 (3H, m), 7.06-7.00 (1H, m), 4.18-4.09 (2H, m), 1.11-1.06(3H, m).

Step 2

2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid

To a mixture of ethanol (179 ml) and2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid ethyl ester (41.8 g) wasadded 2N aqueous sodium hydroxide solution (179 ml), and the mixture wasstirred in an oil bath at 80° C. for 2 hr. The reaction mixture wascooled to room temperature, activated carbon (2.5 g) was added and themixture was stirred for 2.5 hr. The activated carbon was filtered offthrough celite and washed with 50v/v % ethanol-water (100 ml). Thefiltrate was acidified with 2N hydrochloric acid (196 ml). Then, to thismixture was added water (33 ml) and the mixture was stirred at roomtemperature for 2 hr. This suspension was filtered, and the obtainedsolid was air-dried for 2 hr, and dried under reduced pressure at 60° C.to give the title compound (28.6 g, 2 steps 93%).

¹H-NMR (CDCl₃) δ: 8.12-8.08 (1H, m), 7.64-7.59 (1H, m), 7.52-7.47 (1H,m), 7.27-7.24 (1H, m), 7.22-7.16 (2H, m), 7.05-7.00 (1H, m).

Step 3

4-chloro-2-fluoro-fluoren-9-one

To a mixture of phosphorus pentoxide (133 g) and methanesulfonic acid(1300 ml) was added 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid(132.9 g), and the mixture was stirred at 80° C. for 2.5 hr. Thereaction mixture was ice-cooled, water (1300 ml) was slowly addeddropwise, and the mixture was further stirred at room temperature for 1hr. This suspension was filtered, and the obtained solid was washed withwater (300 ml). The solid was mixed with 50 v/v % ethanol-water (1300ml), and the slurry was stirred at room temperature for 1.5 hr, andfiltered. The obtained solid was washed with 50 v/v % ethanol-water (200ml), air-dried for 3 hr, and dried under reduced pressure at 60° C. togive the title compound (121.6 g, 99%).

¹H-NMR (CDCl₃) δ: 8.13-8.10 (1H, m), 7.72-7.69 (1H, m), 7.57-7.53 (1H,m), 7.36-7.30 (2H, m), 7.20-7.17 (1H, m).

Step 4

(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acidethyl ester

To a mixture of dimethylformamide (1000 ml) and4-chloro-2-fluoro-fluoren-9-one (204 g) was added potassium carbonate(36.4 g), and the mixture was stirred in a water bath. To this mixturewas added dropwise trimethyl(trifluoromethyl)silane (156 ml) over 30min, and the mixture was further stirred at room temperature for 30 min.To the reaction mixture was added cesium fluoride (173 g), ethylbromoacetate (75 ml) was added dropwise over 20 min, and the mixture wasstirred at room temperature. Water (1000 ml) was added to the reactionmixture, and the mixture was placed in a separatory funnel, andextracted with ethyl acetate (1000 ml). The organic layer was washedtwice with brine (water:saturated brine=4:1, 1000 ml) and once withsaturated brine (500 ml), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to givethe title compound (360 g). The obtained residue was directly used forthe next reaction without further purification.

¹H-NMR (CDCl₃) δ: 8.30-8.27 (1H, m), 7.73-7.69 (1H, m), 7.57-7.52 (1H,m), 7.43-7.37 (2H, m), 7.25-7.21 (1H, m), 4.11 (2H, q, J=7.1 Hz), 3.60(1H, d, J=15.5 Hz), 3.53 (1H, d, J=15.3 Hz), 1.19 (3H, t, J=7.2 Hz).

Step 5

(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

To a mixture of ethanol (440 ml) and(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acidethyl ester (360 g) was added 2N aqueous sodium hydroxide solution (877ml), and the mixture was stirred at 80° C. for 3.5 hr. The reactionmixture was cooled to room temperature, insoluble material was filteredoff through celite, and washed with water (500 ml) and ethanol (60 ml).Water (120 ml) was added to the filtrate and the mixture was ice-cooled,and formic acid (199 ml) was added dropwise. This suspension was stirredat room temperature overnight, and filtered. The obtained solid waswashed with 25v/v % ethanol-water (400 ml), air-dried overnight, anddried under reduced pressure at 60° C. to give the title compound (285g, 2 steps 90%).

¹H-NMR (CDCl₃) δ: 8.32-8.29 (1H, m), 7.71-7.67 (1H, m), 7.59-7.54 (1H,m), 7.45-7.40 (1H, m), 7.38-7.34 (1H, m), 7.27-7.23 (1H, m), 3.65 (1H,d, J=16.0 Hz), 3.60 (1H, d, J=16.0 Hz).

Step 6

salt of optically active form of(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and(R)-(+)-1-(1-naphthyl)-ethylamine

To a mixture of methyl ethyl ketone (250 ml) and(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid (50g) was added (R)-(+)-1-(1-naphthyl)-ethylamine (11.1 ml), and themixture was stirred at 50° C. for 3 days. This suspension was cooled toroom temperature, further stirred for 4 days, and filtered. The obtainedsolid was dried under reduced pressure to give the title compound (25.5g, 35%). The solid was subjected to derivatization method A fordetermining the optical purity, and the obtained mixture was analyzedunder HPLC analysis condition 1 to find that an isomer with a longretention time was the main component.

-   isomer with short retention time (retention time 22.58 min)-   isomer with long retention time (retention time 22.73 min)    Step 7

optically active form of(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

To a mixture of ethyl acetate (178 ml), and a salt (25.45 g) of anoptically active form of(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and(R)-(+)-1-(1-naphthyl)-ethylamine were added 2N hydrochloric acid (51ml) and water (127 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was partitioned in a separatory funnel. Theorganic layer was washed twice with water (100 ml) and then withsaturated brine (100 ml), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, n-hexane(127 ml) was added to the obtained residue and the mixture was stirredat room temperature for 1 hr. This slurry was filtered, and the obtainedsolid was washed with hexane, and dried under reduced pressure to givethe title compound (16.33 g, 95%).

¹H-NMR (DMSO-D₆) δ: 12.78 (1H, br s), 8.31-8.28 (1H, m), 7.73-7.65 (3H,m), 7.56-7.49 (2H, m), 3.57 (1H, d, J=15.8 Hz), 3.51 (1H, d, J=15.5 Hz).

Step 8

(+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol

To a mixture of dimethylformamide (184 ml) and an optically active form(36.74 g) of(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid wasadded N-ethyldiisopropylamine (20.9 ml), and the mixture was stirred at0° C. Thereto, diphenylphosphoryl azide (23.7 ml) was added dropwiseover 30 min, and the mixture was further stirred at 0° C. for 2 hr. Tothe reaction mixture was added acetic acid (2.86 ml) and the mixture waswarmed to room temperature. t-Butyl alcohol (96 ml) was added, and themixture was stirred at 100° C. for 1 hr. The reaction mixture wasice-cooled, 2N hydrochloric acid (367 ml) was added, placed in aseparatory funnel and the mixture was extracted 3 times with toluene(180 ml). The combined organic layer was successively washed with water(180 ml), 1N aqueous sodium hydroxide solution (180 ml), water (180 ml)and saturated brine (180 ml), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theobtained residue, ethanol (37 ml), tetrahydrofuran (37 ml) and 2Naqueous sodium hydroxide solution (37 ml) were mixed, and the mixturewas stirred at 60° C. for 3 hr. The reaction mixture was cooled to roomtemperature, water (180 ml) was added, and the mixture was placed in aseparatory funnel, and extracted twice with toluene (180 ml). Theorganic layer was washed twice with water (180 ml) and once withsaturated brine (180 ml), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure and theobtained residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=9/1 to 8/2) to give the title compound(21.69 g, 70%).

[α]D=+30.60° (20° C., c=1.00, methanol)

¹H-NMR (CDCl₃) δ: 8.29-8.26 (1H, m), 7.73-7.69 (1H, m), 7.55-7.50 (1H,m), 7.43-7.35 (2H, m), 7.21-7.18 (1H, m), 2.82 (1H, s).

Example 2 Synthesis of(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol(compound No. 595)

Step 1

[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-aceticacid t-butyl ester

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (10 g),N,N-dimethylacetamide (100 ml), potassium carbonate (17.8 g) and t-butylbromoacetate (9.9 ml) were mixed, and the mixture was stirred at roomtemperature for 4 hr. The reaction mixture was filtered through celite.Water and ethyl ether were added to the filtrate, and the mixture waspartitioned in a separatory funnel. The aqueous layer was extracted withethyl ether, and the organic layers were combined. The organic layer waswashed 3 times with water and once with saturated brine, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, hexane (50 ml) was added to the obtained residueand the mixture was stirred. This slurry was filtered, and the obtainedsolid was washed with hexane, and dried under reduced pressure to givethe title compound (12.23 g, 77%).

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, d, J=0.7 Hz), 7.59 (1H, d, J=0.5 Hz), 4.95(2H, s), 1.42 (9H, s), 1.25 (12H, s).

Step 2

optically active form of t-butyl[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate

Sodium hydrogen carbonate (5.54 g), water (33 ml), toluene (100 ml),(+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (10.0 g),t-butyl[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-acetate(15.3 g), palladium(II)acetate (370 mg) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.35 g) were mixed, andpurged with argon. The mixture was stirred at 100° C. for 180 min. Thereaction mixture was cooled to room temperature, water was added, andthe mixture was filtered through celite. The filtered substance wasfurther washed with toluene and water. The filtrate was partitioned in aseparatory funnel. The aqueous layer was extracted with toluene. Thecombined organic layer was washed three times with water and once withsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the obtainedresidue was recrystallized from n-hexane/2-propanol (10:1, 165 ml) togive the title compound (11.1 g, 60%).

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.66 (1H, d, J=0.7 Hz), 7.63 (1H,d, J=0.7 Hz), 7.42-7.37 (2H, m), 7.31-7.25 (2H, m), 7.03 (1H, dd, J=9.5,2.6 Hz), 4.94 (1H, d, J=17.2 Hz), 4.89 (1H, d, J=17.4 Hz), 2.85 (1H, brs), 1.52 (9H, s).

Step 3

optically active form of ethyl2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionate

To a mixture of tetrahydrofuran (80 ml) and an optically active form(10.1 g) of t-butyl[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetatewas added ethyl formate (4.13 ml), and the mixture was stirred at 0° C.To this mixture was added sodium hydride (60w/w % mineral oildispersion, 2.57 g). The reaction mixture was warmed to room temperatureand stirred for 3 hr. The reaction mixture was ice-cooled, 1Nhydrochloric acid was added and the mixture was stirred. Ethyl acetateand water were added thereto, and the mixture was partitioned in aseparatory funnel. The aqueous layer was further extracted with ethylacetate, and the extract was combined with the organic layer obtainedearlier. The organic layer was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give the titlecompound (13.2 g). The obtained residue was directly used for the nextreaction without further purification.

¹H-NMR (DMSO-D₆) δ: 11.98 (1H, br s), 7.98 (1H, br s), 7.97 (1H, d,J=0.5 Hz), 7.77 (1H, d, J=0.7 Hz), 7.66-7.62 (1H, m), 7.44-7.39 (3H, m),7.36-7.32 (1H, m), 7.30-7.24 (1H, m), 7.21 (1H, dd, J=9.9, 2.4 Hz), 4.18(2H, q, J=7.1 Hz), 1.22 (3H, t, J=7.1 Hz).

Step 4

(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol

To a mixture of ethanol (80 ml) and sodium borohydride (16.2 g), asolution of an optically active form (13.2 g) of ethyl2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionatein tetrahydrofuran (80 ml) was added dropwise over 25 min. At this time,the temperature of the reaction mixture was controlled with an ice-bathnot to exceed 30° C. The ice-bath was changed to a water-bath, and themixture was stirred for 17 hr. Then, the water-bath was removed and themixture was further stirred for 4 hr. The reaction mixture wasice-cooled, 2N hydrochloric acid was added and the mixture was stirred.To this mixture were added ethyl acetate and water, and the mixture waspartitioned in a separatory funnel. The aqueous layer was furtherextracted with ethyl acetate, and the extract was combined with theorganic layer obtained earlier. The organic layer was successivelywashed with water and saturated brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=30/1 to 15/1) to give thetitle compound (7.38 g, 84%).

[α]D=+67.50° (20° C., c=1.00, methanol)

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, s), 7.68 (1H, s), 7.66-7.61 (1H, m),7.44-7.37 (3H, m), 7.36-7.31 (1H, m), 7.30-7.26 (1H, m), 7.18 (1H, dd,J=10.0, 2.6 Hz), 4.99-4.94 (2H, m), 4.39-4.32 (1H, m), 3.86-3.76 (4H,m).

The obtained title compound can be crystallized from a solvent(toluene/ethyl acetate (7:1)) containing 1 mol of water per 1 mol of thecompound.

Using the above-mentioned(+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol as anintermediate and by a similar method, compound Nos. 531, 534, 537, 543,544, 545, 548, 549, 551, 565, 566, 607, 610, 672, 674, 675, 682, 685,687, 692, 693, 694, 695, 704 and 705 were synthesized.

Example 3 Synthesis of(+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionicacid (compound No. 538)

Step 1

2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester

Under an argon atmosphere, 4-bromo-3-chlorotoluene (200 g), ethyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (376 g), toluene(1000 ml), water (1000 ml), tripotassium phosphate (412 g) anddichlorobis(triphenylphosphine)palladium(II) (14 g) were added to areaction vessel and the mixture was stirred at 110° C. for 2 hr. Thereaction mixture was cooled to room temperature. The insoluble materialwas filtered off, and washed with water (500 ml) and toluene (500 ml).The filtrate was partitioned in a separatory funnel. The organic layerwas washed twice with water (1000 ml), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure to give the title compound (337 g). The obtained residue wasdirectly used for the next reaction without further purification.

¹H-NMR (CDCl₃) δ: 8.02-7.99 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H,m), 7.28-7.23 (2H, m), 7.13-7.11 (2H, m), 4.17-4.08 (2H, m), 2.38 (3H,s), 1.06 (3H, t, J=7.1 Hz).

Step 2

2′-chloro-4′-methyl-biphenyl-2-carboxylic acid

To a mixture of ethanol (728 ml) and2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester (337 g) wasadded 4N aqueous sodium hydroxide solution (728 ml), and the mixture wasstirred at 80° C. for 2 hr. The reaction mixture was cooled to roomtemperature, activated carbon (17 g) was added and the mixture wasstirred overnight. The activated carbon was filtered off, and washedwith 50v/v % ethanol-water (200 ml). The filtrate was acidified bydropwise addition of acetic acid (500 ml) at room temperature. To thismixture, water (414 ml) was added dropwise at room temperature, and themixture was stirred for 2 hr. This suspension was filtered, and theobtained solid was washed with 40v/v % ethanol-water (250 ml), and driedunder reduced pressure at 80° C. to give the title compound (203 g, 2steps 85%).

¹H-NMR (DMSO-D₆) δ: 12.60 (1H, br s), 7.93-7.89 (1H, m), 7.64-7.58 (1H,m), 7.53-7.47 (1H, m), 7.32-7.29 (1H, m), 7.25-7.21 (1H, m), 7.20-7.13(2H, m), 2.34 (3H, s).

Step 3

4-chloro-2-methyl-fluoren-9-one

To a mixture of phosphorus pentoxide (150 g) and methanesulfonic acid(1500 ml) was added 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid (153g), and the mixture was stirred at 80° C. for 2 hr. The reaction mixturewas cooled to 0° C. While keeping the temperature of the reactionmixture at 90° C. or below, water (1500 ml) was added dropwise, and themixture was further stirred at room temperature for 2 hr. Thissuspension was filtered, and the obtained solid was washed with water(1000 ml). The solid was suspended in 50 v/v % ethanol-water (1500 ml),and the slurry was stirred at room temperature for 2 hr, and filtered.The obtained solid was air-dried for 1 hr and dried under reducedpressure at 80° C. to give the title compound (140.12 g, 99%).

¹H-NMR (DMSO-D₆) δ: 8.10-8.07 (1H, m), 7.69-7.64 (2H, m), 7.49-7.41 (3H,m), 2.36 (3H, s).

Step 4

(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

Under an argon stream, potassium carbonate (18 g) was added to a mixtureof dimethylformamide (500 ml) and 4-chloro-2-methyl-fluoren-9-one (100g). To this mixture, trimethyl(trifluoromethyl)silane (78 ml) was addeddropwise over 80 min, and the mixture was further stirred at roomtemperature for 1 hr. To the reaction mixture was added cesium fluoride(87 g) at room temperature, then ethyl bromoacetate (63 ml) was addeddropwise over 15 min, and the mixture was further stirred at roomtemperature for 4 hr. To the reaction mixture was added water (500 ml),and the aqueous layer was extracted twice with toluene (500 ml). Thecombined organic layer was washed with water (500 ml) and saturatedbrine (500 ml), dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. To the obtainedresidue were added ethanol (220 ml) and 2N aqueous sodium hydroxidesolution (440 ml), and the mixture was stirred at 80° C. for 1 hr. Thereaction mixture was cooled to room temperature, activated carbon (15 g)was added, and the mixture was stirred at room temperature overnight.The activated carbon was filtered off, and washed with 33 v/v %ethanol-water (120 ml). The filtrate was acidified by dropwise additionof acetic acid (151 ml), and the mixture was stirred at room temperatureovernight. This suspension was filtered, the obtained solid was washedwith 33 v/v % ethanol-water (150 ml), and dried under reduced.pressureat 80° C. to give the title compound (136.40 g, 87%).

¹H-NMR (DMSO-D₆) δ: 12.76 (1H, br s), 8.26 (1H, d, J=7.7 Hz), 7.69-7.62(2H, m), 7.53-7.45 (3H, m), 3.50 (1H, d, J=15.5 Hz), 3.43 (1H, d, J=15.5Hz), 2.41 (3H, s).

Step 5

salt of optically active form of(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and(R)-(+)-1-phenylethylamine

Step 5-1 Synthesis of Seed Crystal

To a mixture of isopropyl ether (16 ml) and(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid(0.400 g) was added (R)-(+)-1-phenylethylamine (0.058 ml). The mixturewas stirred at room temperature for 1 hr 40 min. This suspension wasfiltered, and the obtained filtrate was dried under reduced pressure togive a solid (0.240 g). The solid (0.210 g) was suspended in ethylacetate (4.2 ml), and the suspension was stirred at room temperature for1 hr. This suspension was filtered, and the obtained filtered substancewas dried under reduced pressure to give a solid (0.178 g). The solid(0.170 g) was resuspended in ethyl acetate (3.4 ml), and the mixture wasstirred at 50° C. for 1 hr. This suspension was filtered, and theobtained solid was dried under reduced pressure to give the titlecompound (0.137 g). The solid was subjected to derivatization method Afor determining the optical purity, and the obtained mixture wasanalyzed under HPLC analysis condition 1 to find that an isomer with along retention time was the main component.

-   isomer with short retention time (retention time 20.19 min)-   isomer with long retention time (retention time 21.41 min)    Step 5-2

To a mixture of methyl isobutyl ketone (575 ml) and(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid(191.60 g) was added (R)-(+)-1-phenylethylamine (34.81 ml). To thismixture was added a seed crystal, and the mixture was stirred at 50° C.for 3 days. This suspension was filtered, and the obtained solid waswashed with methyl isobutyl ketone (192 ml), and dried under reducedpressure to give the title compound (71.10 g, 28%). The solid wassubjected to derivatization method A for determining the optical purity,and the obtained mixture was analyzed under HPLC analysis condition 1 tofind that an isomer with a long retention time was the main component.

-   isomer with short retention time (retention time 24.11 min)-   isomer with long retention time (retention time 25.43 min)    Step 6

optically active form of(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

To a mixture of ethyl acetate (796 ml) and a salt (159.16 g) of anoptically active form of(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and(R)-(+)-1-phenylethylamine was added 2N hydrochloric acid (318 ml), andthe mixture was stirred at room temperature for 2 hr. The mixture waspartitioned in a separatory funnel. The organic layer was washed twicewith water (600 ml) and once with saturated brine (300 ml), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. n-Hexane was added to the obtained residue andthe mixture was stirred at room temperature for 1 hr. This slurry wasfiltered, and the obtained solid was washed with hexane, and dried underreduced pressure to give the title compound (112.33 g, 95%).

¹H-NMR (DMSO-D₆) δ: 12.75 (1H, br s), 8.26 (1H, d, J=7.7 Hz), 7.71-7.62(2H, m), 7.54-7.45 (3H, m), 3.50 (1H, d, J=15.5 Hz), 3.43 (1H, d, J=15.5Hz), 2.41 (3H, s).

Step 7

(+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol

To a mixture of dimethylformamide (90 ml) and an optically active form(30 g) of(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid wasadded triethylamine (14.1 ml), and the mixture was stirred at 0° C. Asolution of diphenylphosphoryl azide (20.0 ml) in dimethylformamide (60ml) was added dropwise over 20 min, and the mixture was further stirredat 0° C. for 2 hr. To the reaction mixture was added t-butyl alcohol (75ml), and the mixture was stirred at 100° C. for 1 hr. The reactionmixture was ice-cooled, 2N hydrochloric acid (300 ml) was added and themixture was stirred at room temperature overnight. To this mixture wasadded water (100 ml) and the mixture was placed in a separatory funnel.The aqueous layer was extracted twice with toluene (300 ml, 200 ml). Thecombined organic layer was successively washed twice with water (200ml), twice with 1N aqueous sodium hydroxide solution (150 ml) and oncewith saturated brine (150 ml), and dried over anhydrous sodium sulfate.Thereto was added silica gel (6 g) and the mixture was stirred at roomtemperature. The insoluble material was filtered off, and washed withtoluene (500 ml). The filtrate was concentrated under reduced pressureto give the title compound (28.58 g).

[α]D=+22.50° (20° C., c=1.00, methanol)

¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J=7.7 Hz), 7.70-7.69 (1H, m), 7.52-7.47(1H, m), 7.44-7.42 (1H, m), 7.40-7.35 (1H, m), 7.25 (1H, s), 2.82 (1H,br s), 2.41 (3H, s).

Step 8

t-butyl3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionate

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.82 g),acetonitrile (50 ml), cesium fluoride (455.7 mg) and t-butyl acrylate(5.7 ml) were mixed at room temperature, and the mixture was stirred at80° C. for 17.5 hr. The reaction mixture was cooled to room temperature,and concentrated under reduced pressure. To the obtained residue wereadded water and ethyl ether, and the mixture was partitioned in aseparatory funnel. The aqueous layer was further extracted with ethylether, and the organic layers were combined. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=9/1 to 4/6) to give thetitle compound (8.38 g, 87%).

¹H-NMR (CDCl₃) δ: 7.77 (1H, s), 7.71 (1H, s), 4.38 (2H, t, J=6.9 Hz),2.80 (2H, t, J=6.8 Hz), 1.41 (9H, s), 1.31 (12H, s).

Step 9

optically active form of t-butyl3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionate

Tripotassium phosphate (35.7 g), water (60 ml), toluene (240 ml),(+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (28.58 g),t-butyl3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-propionate(41.9 g), palladium(II)acetate (1.89 g) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.905 g) were mixed ina reaction vessel, and purged with argon. The mixture was stirred at100° C. for 3 hr. The reaction mixture was cooled to room temperature,water (180 ml) was added and the mixture was stirred overnight.Insoluble material was filtered off through celite, and washed withethyl acetate (500 ml). The filtrate was partitioned in a separatoryfunnel. The aqueous layer was extracted with ethyl acetate, and theorganic layers were combined. The organic layer was successively washedwith water (250 ml), saturated aqueous sodium hydrogen carbonate (250ml) and saturated brine (200 ml), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure, andthe obtained residue was dissolved in toluene/ethyl acetate (3:1, 270ml). Silica gel (30 g) was added and the mixture was stirred at roomtemperature for 3 hr. The mixture was filtered, and washed withtoluene/ethyl acetate (3:1, 500 ml). The filtrate was concentrated underreduced pressure, isopropyl ether (100 ml) was added to the obtainedresidue and the mixture was stirred at room temperature for 4 hr. Thisslurry was filtered, and the obtained solid was washed with isopropylether (40 ml), and dried under reduced pressure at 50° C. The solid wasmixed with chloroform (27 ml) and the mixture was stirred at roomtemperature for 5 min. Hexane (107 ml) was added, and the mixture wasfurther stirred for 2 hr 50 min. This suspension was filtered, and thefiltered substance was washed with hexane/chloroform (4:1, 40 ml), anddried under reduced pressure at 50° C. to give the title compound (24.75g, 64%).

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.54 (1H, s), 7.51-7.47 (1H, m),7.50 (1H, s), 7.28-7.19 (3H, m), 7.06-7.03 (1H, m), 4.44 (2H, t, J=6.6Hz), 3.16 (1H, br s), 2.88 (2H, t, J=6.5 Hz), 2.41 (3H, s), 1.43 (9H,s).

Step 10

(+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionicacid

To a mixture of 1,4-dioxane (6.7 ml) and an optically active form (1.34g) of t-butyl3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionatewas added trifluoroacetic acid (6.7 ml), and the mixture was stirred atroom temperature for 4 hr. The reaction mixture was concentrated underreduced pressure. Toluene was added to the obtained residue and themixture was concentrated under reduced pressure. To the residue wasadded water (10 ml) and the mixture was extracted twice with ethylacetate (10 ml). The combined organic layer was washed twice with water(10 ml) and once with saturated brine (10 ml), and dried over anhydroussodium sulfate. Insoluble material was filtered off, and the obtainedfiltrate was concentrated under reduced pressure. Toluene was added tothe obtained residue and the mixture was concentrated under reducedpressure. n-Hexane (10 ml) was added to the concentrated residue, andthe slurry was stirred and filtered. The obtained solid was washed withn-hexane, and dried under reduced pressure to give the title compound(1.12 g, 96%).

[α]D=+65.10° (25° C., c=1.00, methanol)

¹H-NMR (DMSO-D₆) δ: 12.40 (1H, br s), 7.93 (1H, s), 7.61-7.56 (1H, m),7.57 (1H, s), 7.41-7.39 (1H, m), 7.30-7.21 (3H, m), 7.13 (1H, br s),7.09-7.08 (1H, m), 4.40 (2H, t, J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz), 2.36(3H, s).

Example 4 Synthesis of(+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyricacid (compound No. 539)

Step 1

4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-butyricacid ethyl ester

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (25.0 g),dimethylformamide (200 ml), potassium carbonate (44.5 g) and ethyl4-bromobutyrate (36.9 ml) were mixed at room temperature and stirred at75° C. for 6 hr. The reaction mixture was cooled to room temperature,and the insoluble material was filtered off through celite. To thefiltrate was added water (150 ml) and the mixture was extracted twicewith ethyl acetate (100 ml, 50 ml). To the aqueous layer was added water(100 ml) again and the mixture was extracted twice with ethyl acetate(50 ml). To the combined organic layer was added n-hexane (100 ml), andthe mixture was washed 3 times with water (100 ml) and once withsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate-5/1 to 1/1) to give the title compound (33.4 g,84%).

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, d, J=0.4 Hz), 7.58 (1H, d, J=0.7 Hz), 4.14(2H, t, J=6.7 Hz), 4.03 (2H, q, J=7.1 Hz), 2.22 (2H, t, J=7.4 Hz),2.04-1.96 (2H, m), 1.25 (12H, s), 1.17 (3H, t, J=7.2 Hz).

Step 2

optically active form of4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyricacid ethyl ester

Tripotassium phosphate (14.86 g), water (30 ml), toluene (60 ml),(+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (9.583 g) and4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-butyricacid ethyl ester (12.08 g) were added to a reaction vessel, and purgedwith argon. To this mixture were added palladium(II)acetate (314 mg) anda solution (30 ml) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl(1.149 g) in toluene and the mixture was stirred at 90° C. for 2 hr. Thereaction mixture was cooled to room temperature, activated carbon (2 g)was added and the mixture was stirred for 30 min. The insoluble materialwas filtered off. The filtrate was partitioned in a separatory funnel.The organic layer was washed twice with water (50 ml) and once withsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure, and the obtainedresidue was recrystallized from isopropyl ether (50 ml) to give thetitle compound (7.926 g, 64%).

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.53-7.51 (1H, m), 7.42 (1H, s),7.27-7.21 (2H, m), 7.20-7.15 (1H, m), 7.12-7.08 (1H, m), 7.04-7.02 (1H,m), 4.18 (2H, t, J=6.7 Hz), 4.14 (2H, q, J=7.1 Hz), 4.03 (1H, brs), 2.41(3H, s), 2.34-2.28 (2H, m), 2.23-2.15 (2H, m), 1.25 (3H, t, J=7.2 Hz).

Step 3

(+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyricacid

To a mixture of ethanol (5.4 ml) and an optically active form (3.55 g)of4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyricacid ethyl ester was added 2N aqueous sodium hydroxide solution (18 ml),and the mixture was stirred at room temperature for 1.5 hr. The reactionmixture was acidified with 2N hydrochloric acid (36 ml). To this mixturewas added water (36 ml), and the mixture was extracted 3 times withethyl acetate (30 ml). The combined organic layer was washed 3 timeswith water (50 ml) and once with saturated brine (50 ml), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give the title compound (3.40 g, 100%).

[α]D=+63.00° (20° C., c=1.00, methanol)

¹H-NMR (DMSO-D₆) δ: 12.21 (1H, br s), 7.98 (1H, s), 7.64-7.59 (1H, m),7.60 (1H, s), 7.44-7.42 (1H, m), 7.33-7.22 (3H, m), 7.17 (1H, br s),7.14-7.12 (1H, m), 4.24 (2H, t, J=6.7 Hz), 2.39 (3H, s), 2.27 (2H, t,J=7.3 Hz), 2.12-2.05 (2H, m).

The obtained compound was crystallized from toluene/ethyl acetate(20:1).

Using the above-mentioned(+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol as anintermediate and by a similar method, compound Nos. 529, 532, 533, 546,550, 574, 575, 576, 605, 606, 663, 686, 690, 691, 696, 697, 699, 700,701, 702, 706 and 707 were synthesized.

Example 5 Synthesis of(−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxamide(compound No. 630)

Step 1

ethyl 4′-chloro-2′-methyl-biphenyl-2-carboxylate

Under an argon atmosphere, a mixture of 2-bromo-5-chloro-toluene (20.55g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (55.23g), toluene (200 ml), water (125 ml), tripotassium phosphate (53.07 g)and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethanecomplex (1.633 g) was stirred with heating under reflux for 1 hr. Thereaction mixture was cooled to room temperature, activated carbon (1 g)was added and the mixture was stirred for 10 min at room temperature.The insoluble material was filtered off, and the filtrate waspartitioned in a separatory funnel. The organic layer was washed twicewith water, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=98/2) to give the title compound (27.20 g, 99%).

¹H-NMR (CDCl₃) δ: 7.98 (1H, dd, J=7.7, 1.1 Hz), 7.56-7.51 (1H, m),7.46-7.42 (1H, m), 7.23-7.22 (1H, m), 7.20-7.16 (2H, m), 7.00 (1H, d,J=7.9 Hz), 4.07 (2H, q, J=7.1 Hz), 2.04 (3H, s), 1.02 (3H, t, J=7.2 Hz).

Step 2

4′-chloro-2′-methyl-biphenyl-2-carboxylic acid

A mixture of ethyl 4′-chloro-2′-methyl-biphenyl-2-carboxylate (27.10 g),ethanol (60 ml) and 1N aqueous sodium hydroxide solution (120 ml) wasstirred at 100° C. for 2 hr. To the reaction mixture was added 8Naqueous sodium hydroxide m solution (10 ml), and the mixture was furtherstirred at 100° C. for 1 hr. The reaction mixture was cooled to roomtemperature. The insoluble material was filtered off, and washed with 33v/v % ethanol-water (100 ml). The filtrate was adjusted to pH 2 withformic acid (23 ml) and the mixture was stirred at room temperature for1 hr. This suspension was filtered, and the obtained solid was air-driedfor 1 hr and dried under reduced pressure at 60° C. to give the titlecompound (22.082 g, 91%).

¹H-NMR (DMSO-D₆) δ: 12.64 (1H, s), 7.89 (1H, dd, J=7.8, 1.0 Hz),7.63-7.58 (1H, m), 7.52-7.48 (1H, m), 7.33-7.32 (1H, m), 7.26-7.19 (2H,m), 7.05 (1H, d, J=8.2 Hz), 2.00 (3H, s).

Step 3

2-chloro-4-methyl-fluoren-9-one

Under anhydrous calcium chloride drying conditions, a mixture of4′-chloro-2′-methyl-biphenyl-2-carboxylic acid (21.60 g) and Eaton'sreagent (7.7 w/w % solution of phosphorus pentoxide in methanesulfonicacid) (170 ml) was stirred at 100° C. for 2.5 hr. The reaction mixturewas ice-cooled, water (500 ml) was slowly added dropwise, and themixture was further stirred at room temperature for 10 min. Thissuspension was filtered, the obtained solid was mixed with 30 v/v %aqueous ethanol solution (200 ml), and the slurry was stirred at roomtemperature for 10 min, and filtered. The obtained solid was air-driedand dried under reduced pressure at 80° C. to give the title compound(19.744 g, 99%).

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.60-7.57 (1H, m), 7.52-7.46 (2H,m), 7.32-7.27 (1H, m), 7.25-7.23 (1H, m), 2.56 (3H, s).

Step 4

2-chloro-4-methyl-9-trifluoromethyl-9H-fluoren-9-ol

Under anhydrous calcium chloride drying conditions,2-chloro-4-methyl-fluoren-9-one (18.627 g), potassium carbonate (3.372g) and dimethylformamide (100 ml) were mixed,trimethyl(trifluoromethyl)silane (16 ml) was added dropwise over 25 minat room temperature with stirring, and the mixture was further stirredat room temperature for 14 min. To this mixture, a 1M solution (122 ml)of tetrabutylammonium fluoride in tetrahydrofuran was added dropwiseover 6 min. To the reaction mixture was added aqueous ammonium chloride(400 ml), and the mixture was extracted with ethyl acetate (200 ml). Theorganic layer was washed once with water (100 ml), once with saturatedaqueous sodium hydrogen carbonate and 3 times with water, andconcentrated under reduced pressure. The obtained residue was dissolvedin methanol (200 ml), activated carbon (1.5 g) was added, and themixture was stirred at room temperature for 10 min. The mixture wasfiltered, and the filtrate was concentrated under reduced pressure togive the title compound (24.689 g). The obtained residue was directlyused for the next reaction without further purification.

¹H-NMR (CDCl₃) δ: 7.78-7.75 (1H, m), 7.74-7.70 (1H, m), 7.55-7.53 (1H,m), 7.52-7.47 (1H, m), 7.40-7.35 (1H, m), 7.27-7.25 (1H, m), 2.80 (1H,brs), 2.64 (3H, s).

Step 5

2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid

To a mixture of 2-chloro-4-methyl-9-trifluoromethyl-9H-fluoren-9-ol(2.987 g), pyridine (6 ml) and water (24 ml) was added potassiumpermanganate (7.902 g) at 100° C., and the mixture was stirred for 2 hr.To this mixture were added further potassium permanganate (4.70 g) andpyridine (6 ml) and the mixture was stirred at 100° C. for 2 hr.Potassium permanganate (4.70 g) was further added and the mixture wasstirred at 100° C. for 2 hr. This operation was repeated twice. Thereaction mixture was cooled to room temperature, and the insolublematerial was filtered off and washed with water (50 ml). The filtratewas adjusted to pH 1 with 6N hydrochloric acid, and extracted with ethylacetate (200 ml). The organic layer was successively washed with waterand saturated brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure and the obtainedresidue was treated with hexane/ethyl acetate mixed solution(hexane:ethyl acetate=9:1) (30 ml). This slurry was filtered, and theobtained solid was dried to give the title compound (2.509 g, 76%).

¹H-NMR (DMSO-D₆) δ: 13.91 (1H, br s), 8.22-8.19 (1H, m), 7.87 (1H, d,J=2.0 Hz), 7.81-7.79 (1H, m), 7.72-7.68 (1H, m), 7.57-7.51 (2H, m),7.51-7.46 (1H, m).

Step 6

salt of optically active form of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and(S)-(−)-1-phenylethylamine

Step 6-1 Synthesis of Seed Crystal

To a solution of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid(0.100 g) in ethyl acetate (0.50 ml) was added(S)-(−)-1-phenylethylamine (0.040 ml), and the mixture was stirred atroom temperature for 2 days. This suspension was filtered, and theobtained solid was dried under reduced pressure to give the titlecompound (0.062 g, containing 8 w/w % ethyl acetate, 41%). The solid wasanalyzed under HPLC analysis condition 2 to find that the isomer with ashort retention time was the main component.

-   isomer with short retention time (retention time 20.35 min)-   isomer with long retention time (retention time 21.10 min)

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, d, J=7.2 Hz), 8.29 (3H, br s), 7.61-7.57(1H, m), 7.51-7.48 (2H, m), 7.45-7.32 (7H, m), 7.30 (1H, br s), 4.38(1H, q, J=6.8 Hz), 1.49 (3H, d, J=6.7 Hz).

Step 6-2

To a solution of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid(0.972 g) in ethyl acetate (5.0 ml) were added(S)-(−)-1-phenylethylamine (0.38 ml) and a seed crystal of a salt of anoptically active form of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and(S)-(−)-1-phenylethylamine, and the mixture was stirred at roomtemperature for 2 days. This suspension was filtered, and the obtainedsolid was dried under reduced pressure to give the title compound (0.608g, containing 16 w/w % ethyl acetate, 38%). The solid was analyzed underHPLC analysis condition 2 to find that the isomer with a short retentiontime was the main component.

-   isomer with short retention time (retention time 20.31 min)-   isomer with long retention time (retention time 21.06 min)

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, d, J=7.1 Hz), 8.34 (3H, br s), 7.61-7.57(1H, m), 7.51-7.48 (2H, m), 7.46-7.32 (7H, m), 7.30 (1H, br s), 4.38(1H, q, J=6.8 Hz), 1.50 (3H, d, J=6.8 Hz).

Step 7

optically active form of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid

A salt of an optically active form of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and(S)-(−)-1-phenylethylamine (0.575 g) was dissolved in ethyl acetate, andthe mixture was placed in a separatory funnel, hydrochloric acid wasadded, and the mixture was partitioned. The organic layer was washedwith water, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give the titlecompound (0.357 g).

¹H-NMR (DMSO-D₆) δ: 13.90 (1H, br s), 8.22-8.19 (1H, m), 7.87 (1H, d,J=2.0 Hz), 7.81-7.79 (1H, m), 7.72-7.68 (1H, m), 7.57-7.46 (3H, m).

Step 8

1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.0 g),N,N-dimethylacetamide (50 ml), potassium carbonate (5.3 g) and ethyliodide (2.1 ml) were mixed, and the mixture was stirred at 60° C.overnight. The reaction mixture was cooled to room temperature, water(100 ml) and ethyl ether (100 ml) were added, and the mixture waspartitioned in a separatory funnel. The aqueous layer was furtherextracted with ethyl ether (100 ml), and the organic layers werecombined. The organic layer was washed 3 times with water (100 ml) andonce with saturated brine (100 ml), dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated under reduced pressure,hexane (50 ml) was added to the obtained residue and the mixture waspartitioned in a separatory funnel. The organic layer was washed 3 timeswith water (40 ml) and once with saturated brine (40 ml), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give the title compound (2.1691 g, 38%).

¹H-NMR (CDCl₃) δ: 7.79 (1H, s), 7.70 (1H, s), 4.19 (2H, q, J=7.3 Hz),1.49 (3H, t, J=7.3 Hz), 1.32 (12H, s).

Step 9

optically active form of2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylicacid

Under an argon atmosphere, an optically active form (0.100 g) of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid,1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(0.133 g), tripotassium phosphate (0.191 g), palladium(II)acetate(0.0034 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0123 g),dioxane (3 ml) and water (0.6 ml) were mixed, and the mixture wasstirred at 100° C. for 1 hr. The reaction mixture was cooled to roomtemperature, hydrochloric acid and ethyl acetate were added, and themixture was partitioned in a separatory funnel. The organic layer waswashed twice with water and once with saturated brine, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the obtained residue was treated withhexane/ethyl acetate mixed solution (hexane:ethyl acetate=1:2,2 ml).This slurry was filtered, and the obtained solid was dried to give thetitle compound (0.075 g, 63%).

¹H-NMR (DMSO-D₆) δ: 13.60 (1H, s), 8.43 (1H, s), 8.18-8.15 (1H, m), 8.01(1H, d, J=0.7 Hz), 8.00 (1H, d, J=1.6 Hz), 7.97-7.95 (1H, m), 7.70-7.66(1H, m), 7.53-7.48 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 4.17 (2H,q, J=7.3 Hz), 1.43 (3H, t, J=7.3 Hz).

Step 10

(−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxamide

To a mixture of an optically active form (0.051 g) of2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylicacid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038g), 1-hydroxybenzotriazole hydrate (0.030 g), ammonium chloride (0.022g) and dimethylformamide (1 ml) was added triethylamine (0.055 ml), andthe mixture was stirred at room temperature overnight. To the reactionmixture was added ethyl acetate (10 ml), and the organic layer wassuccessively washed once with hydrochloric acid, once with water, twicewith saturated aqueous sodium hydrogen carbonate, 3 times with water andonce with saturated brine. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure to give the title compound (0.043 g, 85%).

[α]D=−3.00° (20° C., c=0.20, methanol)

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, s), 8.14 (1H, br s), 7.98 (1H, J=0.7 Hz),7.93-7.90 (1H, m), 7.85-7.83 (1H, m), 7.74 (1H, br s), 7.70 (1H, d,J=1.5 Hz), 7.67-7.64 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.30(1H, s), 4.17 (2H, q, J=7.3 Hz), 1.42 (3H, t, J=7.3 Hz).

Using the above-mentioned optically active form of2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid as anintermediate and by a similar method, compound Nos. 629, 659, 660, 667and 668 were synthesized.

Example 6 Synthesis of(−)-1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylicacid dimethylamide (compound No. 153)

Step 1

2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate

Under a nitrogen atmosphere, to a mixture of methyl4-bromo-3-methylbenzoate (2.291 g), ethyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.313 g),toluene (20 ml), water (10 ml) and tripotassium phosphate (4.246 g) wasadded tetrakis(triphenylphosphine)palladium(0) (0.578 g) at roomtemperature, and the mixture was stirred with heating under refluxovernight. The reaction mixture was cooled to room temperature, andpartitioned in a separatory funnel. The organic layer was successivelywashed with water and saturated brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=95/5) to give the titlecompound (2.404 g, 81%)

¹H-NMR (CDCl₃) δ: 8.03-7.99 (1H, m), 7.94-7.91 (1H, m), 7.89-7.85 (1H,m), 7.59-7.53 (1H, m), 7.49-7.43 (1H, m), 7.21-7.18 (1H, m), 7.17-7.14(1H, m), 4.07-4.01 (2H, m), 3.93 (3H, s), 2.11 (3H, s), 0.98-0.93 (3H,m).

Step 2

2′-methyl-biphenyl-2,4′-dicarboxylic acid

A mixture of 2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate(2.404 g), ethanol (12 ml) and 4N aqueous sodium hydroxide solution (6ml) was stirred at 100° C. overnight. After completion of the reaction,the reaction mixture was concentrated under reduced pressure, and water(50 ml) was added to the obtained residue. This mixture was adjusted topH 1 with 6N hydrochloric acid (5 ml), ethanol (10 ml) was added, andthe mixture was stirred at room temperature for 10 min. This suspensionwas filtered, the obtained solid was washed with 20v/v % ethanol-water(10 ml), air-dried, and dried under reduced pressure at 80° C. to givethe title compound (1.957 g, 95%).

¹H-NMR (DMSO-D₆) δ: 12.74 (2H, br s), 7.92 (1H, dd, J=7.8, 1.3 Hz),7.82-7.80 (1H, m), 7.76 (1H, dd, J=7.9, 1.6 Hz), 7.65-7.60 (1H, m),7.54-7.49 (1H, m), 7.22 (1H, dd, J=7.7, 1.2 Hz), 7.15 (1H, d, J=7.9 Hz),2.06 (3H, s).

Step 3

4-methyl-9-oxo-9H-fluorene-2-carboxylic acid

A mixture of 2′-methyl-biphenyl-2,4′-dicarboxylic acid (1.94 g) andpolyphosphoric acid (50 g) was stirred at 180° C. for 3 hr. The reactionmixture was cooled to room temperature, water (100 ml) was slowly addeddropwise, and the mixture was further stirred at room temperature for 10min. This suspension was filtered, and the obtained solid wassuccessively washed with water (50 ml) and 50 v/v % aqueous methanolsolution (50 ml). The obtained solid was air-dried, and dried underreduced pressure at 80° C. to give the title compound (1.745 g, 97%).

¹H-NMR (DMSO-D₆) δ: 12.98 (1H, br s), 8.00-7.99 (1H, m), 7.88 (1H, d,J=1.6 Hz), 7.86 (1H, d, J=7.4 Hz), 7.71-7.66 (2H, m), 7.49-7.45 (1H, m),2.65 (3H, s).

Step 4

methyl 4-methyl-9-oxo-9H-fluorene-2-carboxylate

Under anhydrous calcium chloride drying conditions,4-methyl-9-oxo-9H-fluorene-2-carboxylic acid (1.745 g), potassiumcarbonate (3.03 g) and dimethylformamide (20 ml) were mixed. To thismixture was added methyl iodide (0.92 ml) at room temperature, and themixture was stirred for 3 hr 15 min. To the reaction mixture was addedwater (60 ml), and the mixture was stirred at room temperature for 30min. The mixture was filtered and the obtained solid was air-dried anddried under reduced pressure at 80° C. to give the title compound (1.778g, 96%).

¹H-NMR (CDCl₃) δ: 8.17 (1H, s), 8.01 (1H, s), 7.76-7.70 (2H, m),7.58-7.52 (1H, m), 7.40-7.35 (1H, m), 3.94 (3H, s), 2.67 (3H, s).

Step 5

methyl 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate

Under an argon atmosphere, methyl4-methyl-9-oxo-9H-fluorene-2-carboxylate (1.009 g),trimethyl(trifluoromethyl)silane (0.89 ml) and dimethylformamide (50 ml)were mixed, lithium acetate (0.027 g) was added with stirring at roomtemperature, and the mixture was further stirred at room temperature for30 min. Acetic acid (0.7 ml) and a 1M solution (6 ml) oftetrabutylammonium fluoride in tetrahydrofuran were added, and themixture was further stirred at room temperature for 15 min. To thereaction mixture was added aqueous sodium hydrogen carbonate (300 ml),and the mixture was extracted twice with ethyl acetate (50 ml). Thecombined organic layer was washed once with saturated aqueous sodiumhydrogen carbonate, 4 times with water and once with saturated brine,and concentrated under reduced pressure. To the obtained residue wasadded hexane/ethyl acetate (8:2, 10 ml) and the mixture was stirred for10 min. This slurry was filtered, and the obtained solid was dried togive the title compound (1.000 g, 78%).

¹H-NMR (CDCl₃) δ: 8.20-8.19 (1H, m), 7.98-7.96 (1H, m), 7.86 (1H, d,J=7.7 Hz), 7.79-7.75 (1H, m), 7.56-7.51 (1H, m), 7.46-7.40 (1H, m), 3.93(3H, s), 2.84 (1H, s), 2.71 (3H, s).

Step 6

9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid

A mixture of methyl9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate (1.000g), tetrahydrofuran (4 ml), methanol (6 ml) and 4N aqueous sodiumhydroxide solution (1.6 ml) was stirred with heating under reflux for 3hr. The reaction mixture was cooled to room temperature, andconcentrated under reduced pressure. Water (30 ml) was added to theobtained residue, and the mixture was adjusted to pH 1 with 6Nhydrochloric acid (2 ml), and extracted with ethyl acetate (30 ml). Theorganic layer was successively washed with water and saturated brine.After addition of anhydrous magnesium sulfate and activated carbon (0.2g), the mixture was stirred at room temperature for 10 min. Theinsoluble material was filtered off, and the filtrate was concentratedunder reduced pressure to give the title compound (1.053 g). The residuewas directly used for the next reaction without further purification.

¹H-NMR (DMSO-D₆) δ: 13.07 (1H, br s), 8.06-8.03 (1H, m), 7.97-7.91 (2H,m), 7.74-7.71 (1H, m), 7.61-7.56 (1H, m), 7.51-7.46 (1H, m), 7.33 (1H,s), 2.70 (3H, s).

Step 7

salt of racemic9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(R)-(+)-1-phenylethylamine

A mixture of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid(0.159 g), (R)-(+)-1-phenylethylamine (0.066 ml), and ethyl acetate (2ml) was concentrated under reduced pressure, ethyl acetate was added tothe residue and the mixture was concentrated under reduced pressureagain to give the title compound (0.229 g).

Step 8

salt of optically active form (enantiomer with long retention time underHPLC analysis condition 3) of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(R)-(+)-1-phenylethylamine

Salt (0.010 g) of the racemic9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(R)-(+)-1-phenylethylamine obtained in Step 7 was dissolved in ethylacetate (0.2 ml) and the mixture was stood at room temperatureovernight. The obtained solid was collected by filtration, and driedunder reduced pressure to give the title compound (0.0017 g). The solidwas analyzed under HPLC analysis condition 3 to find that an isomer witha long retention time was the main component.

-   isomer with short retention time (retention time 23.27 min)-   isomer with long retention time (retention time 25.39 min)    Step 9

salt of optically active form (enantiomer with short retention timeunder HPLC analysis condition 3) of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(S)-(−)-1-phenylethylamine

Step 9-1 Synthesis of Seed Crystal

To a mixture of a salt (0.141 g) of the racemic9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(R)-(+)-1-phenylethylamine obtained in Step 7 and ethyl acetate (0.70ml) was added a salt of an optically active form (enantiomer with longretention time under HPLC analysis condition 3) of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(R)-(+)-1-phenylethylamine obtained in Step 8 as a seed crystal, and themixture was stirred at room temperature for 30 min. Ethyl acetate (0.7ml) was added to the mixture, and the mixture was further stirred atroom temperature for 2 hr. This suspension was filtered, and theobtained solid was washed with ethyl acetate (4 ml). The filtrate wassuccessively washed with 1N hydrochloric acid and water, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give a residue (0.046 g). The residue wasdissolved in ethyl acetate (0.50 ml), (S)-(−)-1-phenylethylamine (0.019ml) was added, and the mixture was stirred at room temperatureovernight. This suspension was filtered, and the obtained solid waswashed with ethyl acetate (2 ml), and dried. The solid was further mixedwith ethyl acetate (0.5 ml), and the mixture was stirred at 70° C. for30 min, and further at room temperature for 2 hr. This suspension wasfiltered, and the obtained solid was washed with ethyl acetate (2 ml),and dried to give the title compound (0.0357 g). The solid was analyzedunder HPLC analysis condition 3 to find that an isomer with a shortretention time was the main component.

-   isomer with short retention time (retention time 23.57 min)-   isomer with long retention time (retention time 25.65 min)    Step 9-2

To a solution of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid(1.053 g) in ethyl acetate (15 ml) were added at 50° C.(S)-(−)-1-phenylethylamine (0.200 ml) and a seed crystal of a salt of anoptically active form (enantiomer with short retention time under HPLCanalysis condition 3) of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(S)-(−)-1-phenylethylamine obtained in Step 9-1, and the mixture wasstirred at 50° C. for 5 min and at room temperature for 4 hr. Thissuspension was filtered, and the obtained solid was dried under reducedpressure to give the title compound (0.400 g). The solid was analyzedunder HPLC analysis condition 3 to find that an isomer with a shortretention time was the main component.

-   isomer with short retention time (retention time 23.49 min)-   isomer with long retention time (retention time 25.52 min)    Step 10

optically active form of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid

Salt (0.390 g) of an optically active form (enantiomer with shortretention time under HPLC analysis condition 3) of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(S)-(−)-1-phenylethylamine was mixed with ethyl acetate (10 ml),hydrochloric acid was added, and the mixture was partitioned. Theorganic layer was successively washed with water and saturated brine,dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give the title compound (0.310g).

¹H-NMR (DMSO-D₆) δ: 13.10 (1H, br s), 8.06-8.03 (1H, m), 7.97-7.91 (2H,m), 7.75-7.71 (1H, m), 7.61-7.56 (1H, m), 7.51-7.46 (1H, m), 7.35 (1H,s), 2.70 (3H, s).

Step 11

t-butyl 3-dimethylcarbamoyl-azetidine-1-carboxylate

Under a nitrogen atmosphere, triethylamine (1.2 ml) was added to amixture of 1-(t-butyloxycarbonyl)-azetidine-3-carboxylic acid (0.804 g),dimethylamine hydrochloride (0.489 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.997 g),1-hydroxybenzotriazole hydrate (0.796 g), and dimethylformamide (8 ml),and the mixture was stirred at room temperature for 3 days. To thereaction mixture was added ethyl acetate (30 ml), and the mixture wassuccessively washed once with water, once with hydrochloric acid, oncewith water, twice with saturated aqueous sodium hydrogen carbonate andtwice with water. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure to give the title compound (0.364 g, 40%).

¹H-NMR (CDCl₃) δ: 4.17 (2H, br s), 4.05 (2H, t, J=8.5 Hz), 3.52-3.43(1H, m), 2.97 (3H, s), 2.88 (3H, s), 1.43 (9H, s).

Step 12

azetidine-3-carboxylic acid dimethylamide hydrochloride

A mixture of t-butyl 3-dimethylcarbamoyl-azetidine-1-carboxylate (0.365g) and 4N hydrogen chloride/dioxane solution (5 ml) was stirred at roomtemperature for 5 hr 15 min. The reaction mixture was concentrated underreduced pressure, dioxane was added to the obtained residue and themixture was concentrated again under reduced pressure. The obtainedresidue was dried under reduced pressure at 60° C. to give the titlecompound (0.290 g). The obtained residue was directly used for the nextreaction without further purification.

¹H-NMR (DMSO-D₆) δ: 9.38 (1H, br s), 8.95 (1H, br s), 4.10-3.99 (4H, m),3.94-3.85 (1H, m), 2.85 (3H, s), 2.82 (3H, s).

Step 13

(−)-1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylicacid dimethylamide

To a mixture of an optically active form (0.080 g) of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid,azetidine-3-carboxylic acid dimethylamide hydrochloride (0.060 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.065 g),1-hydroxybenzotriazole hydrate (0.052 g) and dimethylformamide (2 ml)was added triethylamine (0.073 ml), and the mixture was stirred at roomtemperature for 3 hr. To the reaction mixture was added ethyl acetate(15 ml), and the mixture was successively washed once with hydrochloricacid, once with water, twice with saturated aqueous sodium hydrogencarbonate and 3 times with water. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the obtained residue was treated with ethylether. This slurry was filtered and the obtained solid was dried to givethe title compound (0.054 g, 50%).

[α]D=−12.53° (25° C., c=0.744, methanol) ¹H-NMR (CDCl₃) δ: 7.85-7.74(3H, m), 7.54-7.48 (1H, m), 7.45-7.38 (2H, m), 4.74-4.64 (1H, m),4.43-4.32 (2H, m), 4.25-4.11 (1H, m), 3.94-3.86 (1H, m), 3.65-3.54 (1H,m), 2.98 (3H, s), 2.91 (3H, s), 2.64 (3H, s).

Using the above-mentioned optically active form of9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid as anintermediate and by a similar method, compound Nos. 136 and 152 weresynthesized.

Example 7 Synthesis of1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one(compound No. 430)

Step 1

2-chloro-5-methoxy-pyridine

Under a nitrogen atmosphere, potassium carbonate (5.52 g) was added to amixture of 2-chloro-5-hydroxy-pyridine (2.591 g), methyl iodide (1.50ml) and dimethylformamide (26 ml), and the mixture was stirred at roomtemperature for 18 hr. To the reaction mixture was added ethyl acetateand the mixture was placed in a separatory funnel. The organic layer waswashed 4 times with aqueous ammonium chloride, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure to give the title compound (2.403 g, 84%).

¹H-NMR (CDCl₃) δ: 8.07 (1H, d, J=3.0 Hz), 7.24 (1H, dd, J=8.8, 0.7 Hz),7.20 (1H, dd, J=8.6, 3.0 Hz), 3.87 (3H, s).

Step 2

2-(5-methoxy-pyridin-2-yl)-benzoic acid diethylamide

Under an argon atmosphere, a mixture of tripotassium phosphate (6.24 g)and water (15 ml) was added to a mixture of 2-chloro-5-methoxy-pyridine(2.05 g), 2-(diethylcarbamoyl)benzeneboronic acid (4.65 g),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethanecomplex (0.584 g) and toluene (30 ml), and the mixture was stirred at80° C. for 2 hr. The reaction mixture was cooled to room temperature,water (20 ml), citric acid (2.2 g) and ethyl acetate were added and themixture was stirred and filtered through celite. The filtrate waspartitioned in a separatory funnel. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=1/1 to 1/2) to give a roughly purified product(1.144 g) of the title compound. This product was directly used for thenext reaction without further purification.

¹H-NMR (CDCl₃) δ: 8.33 (1H, d, J=2.9 Hz), 7.68 (1H, dd, J=7.7, 1.3 Hz),7.60 (1H, d, J=8.6 Hz), 7.48-7.32 (3H, m), 7.25-7.15 (1H, m), 3.88 (3H,s), 3.32-2.78 (4H, m), 1.07 (3H, t, J=7.1 Hz), 0.81 (3H, t, J=7.2 Hz).

Step 3

3-methoxy-indeno[1,2-b]pyridin-5-one

Under an argon atmosphere, a 2.66M solution (1.96 ml) of n-butyllithiumin n-hexane was added to a solution of N,N-diisopropylamine (0.734 ml)in tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at 0°C. for 30 min. To this mixture was added a solution (10 ml) of2-(5-methoxy-pyridin-2-yl)-benzoic acid diethylamide (1.14 g) intetrahydrofuran at 0° C. and the mixture was stirred at 0° C. for 30min, and further at room temperature for 1 hr. To the reaction mixturewas added aqueous ammonium chloride solution and the mixture was placedin a separatory funnel, and separated into layers by adding ethylacetate. The organic layer was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure and the obtainedresidue was treated with ethyl ether at room temperature for 1 hr. Thisslurry was filtered, and the obtained solid was dried to give the titlecompound (0.183 g, 22%). The filtrate was concentrated under reducedpressure and the obtained residue was treated with ethyl ether at roomtemperature for 20 min. This slurry was filtered, and the obtained solidwas dried to further give the title compound (0.128 g, 15%). Thefiltrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=3/1) to further give the title compound (0.134 g,16%).

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, d, J=2.8 Hz), 7.73-7.64 (3H, m), 7.60 (1H,d, J=3.0 Hz), 7.46-7.42 (1H, m), 3.91 (3H, s).

Step 4

3-hydroxy-indeno[1,2-b]pyridin-5-one

[

118]

Under an argon atmosphere, 3-methoxy-indeno[1,2-b]pyridin-5-one (0.545g) and pyridinium chloride (5.89 g) were mixed with pyridine (1.0 ml).The reaction mixture was stirred with heating at 180° C. for 30 minwhile evaporating pyridine, and further stirred with heating at 200° C.for 4 hr. The mixture was cooled to room temperature, water was addedand the mixture was stirred for 30 min. This slurry was filtered, andthe obtained solid was dried under reduced pressure to give the titlecompound (0.054 g). The obtained solid was used for the next reactionwithout further purification.

¹H-NMR (DMSO-D₆) δ: 10.53 (1H, br s), 8.19 (1H, d, J=2.8 Hz), 7.68-7.61(3H, m), 7.43-7.38 (1H, m), 7.29 (1H, d, J=2.6 Hz).

Step 5

3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-indeno[1,2-b]pyridin-5-one

3-Hydroxy-indeno[1,2-b]pyridin-5-one (0.0500 g), di-t-butylazodicarboxylate (0.087 g) and triphenylphosphine (0.10 g) were mixedwith tetrahydrofuran (1.0 ml), 1-(2-hydroxy-ethyl)-2-pyrrolidone (0.043ml) was added thereto, and the mixture was stirred at room temperaturefor 1 day. The mixture was purified by preparative thin layerchromatography (silica gel, eluent: ethyl acetate/methanol=10/1) to givethe title compound (0.0386 g, 49%).

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J=2.8 Hz), 7.73-7.64 (3H, m), 7.63 (1H,d, J=2.8 Hz), 7.47-7.42 (1H, m), 4.27 (2H, t, J=5.4 Hz), 3.57 (2H, t,J=5.4 Hz), 3.49-3.44 (2H, m), 2.25-2.19 (2H, m), 1.97-1.87 (2H, m).

Step 6

1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one

3-[2-(2-Oxo-pyrrolidin-1-yl)-ethoxy]-indeno[1,2-b]pyridin-5-one (0.0376g) and potassium carbonate (0.001 g) were mixed with dimethylformamide(1.0 ml), and the mixture was stirred at 0° C. To this mixture was addedtrimethyl(trifluoromethyl)silane (0.035 ml), and the mixture was stirredat 0° C. for 1 hr. Trimethyl(trifluoromethyl)silane (0.018 ml) wasfurther added, and the mixture was stirred at 0° C. for 1 hr. To thereaction mixture was added acetic acid (0.010 ml), then a 1M solution(0.12 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added,and the mixture was stirred at 0° C. for 30 min. To the reaction mixturewas added ethyl acetate (20 ml), and the mixture was placed in aseparatory funnel. The organic layer was washed 3 times with water (10ml) and once with saturated brine (10 ml). The organic layer was driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bypreparative thin layer chromatography (silica gel, eluent:n-hexane/ethyl acetate=7/3) to give the title compound (0.0389 g, 68%).

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J=2.8 Hz), 7.82-7.78 (1H, m), 7.71-7.66(1H, m), 7.60-7.54 (2H, m), 7.50 (1H, s), 7.48-7.43 (1H, m), 4.25 (2H,t, J=5.4 Hz), 3.59 (2H, t, J=5.4 Hz), 3.51-3.45 (2H, m), 2.26-2.19 (2H,m), 1.97-1.88 (2H, m).

Example 8 Synthesis of optically active form of(4-bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acidmethyl ester (compound No. 451) and the like

Step 1

salt of optically active form of(4-bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid and(S)-(−)-1-phenylethylamine

(4-Bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid(0.176 g) and (S)-(−)-1-phenylethylamine (0.057 ml) were mixed withethyl acetate (1 ml). The mixture was concentrated under reducedpressure. To the obtained residue was added ethyl acetate, and themixture was concentrated under reduced pressure to give a residue (0.233g). Under a nitrogen atmosphere, the residue (0.160 g) and ethyl acetate(2.0 ml) were mixed. The mixture was stirred with heating at 80° C.until insoluble material was solved, and stirred at room temperatureovernight. This suspension was filtered to give a solid (0.044 g). Thesolid was mixed with ethyl ether/ethyl acetate (1:1, 1 ml), and themixture was stirred at room temperature for 1 hr. This suspension wasfiltered, and the obtained solid was washed with ethyl ether/ethylacetate (1:1, 2 ml). The obtained solid was dried under reduced pressureto give the title compound (0.023 g). The solid was analyzed under HPLCanalysis condition 2 to find that an isomer with a long retention timewas the main component.

-   isomer with short retention time (retention time 16.50 min)-   isomer with long retention time (retention time 17.58 min)

Using the salt as an intermediate, compound Nos. 451, 467, 474, 475 and477 were synthesized.

Example 9 Synthesis of optically active form of4-[9-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)-9-trifluoromethyl-9H-fluoren-2-yloxy]-butyricacid (compound No. 504) and the like

Step 1

salt of optically active form of4-(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acidand (S)-(−)-1-(4-methylphenyl)ethylamine

4-(4-Chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acid(0.100 g) and isopropyl ether (2.0 ml) were mixed,(S)-(−)-1-(4-methylphenyl)ethylamine (0.0189 ml) was added, and themixture was stirred at room temperature for 17 hr. This suspension wasfiltered to give a salt (0.0403 g) of an optically active form of4-(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acidand (S)-(−)-1-(4-methylphenyl)ethylamine. The solid was analyzed underHPLC analysis condition 2 to find that an isomer with a long retentiontime was the main component.

-   isomer with short retention time (retention time 19.97 min)-   isomer with long retention time (retention time 22.06 min)

Using this salt as an intermediate, compound Nos. 504, 553, 554, 561,573, 577, 604, 624, 669, 676, 678, 679, 680, 681, 683, 684, 688, 689 and698 were synthesized.

Example 10 Synthesis of optically active form of(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acidmethyl ester (compound No. 481) and the like

Step 1

salt of optically active form of(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acidand (S)-(−)-1-phenylethylamine

Under a nitrogen atmosphere, (S)-(−)-1-phenylethylamine (0.011 ml) wasadded to a mixture of(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid(0.100 g) and isopropyl ether (5.0 ml), and the mixture was stirred atroom temperature overnight. This suspension was filtered, and theobtained solid was dried under reduced pressure to give the titlecompound (0.0414 g). The solid was analyzed under HPLC analysiscondition 2 to find that an isomer with a long retention time was themain component.

-   isomer with short retention time (retention time 15.67 min)-   isomer with long retention time (retention time 16.39 min)

Using this salt as an intermediate, compound Nos. 481, 540, 541, 542,552, 581, 582, 588, 589, 614 and 619 were synthesized.

Example 11 Synthesis of optically active form of4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acidmethyl ester (compound No. 647) and the like

Salt of optically active form of4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(S)-(−)-1-phenylethylamine

Step 1-1 Synthesis of Seed Crystal

To a mixture of4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid(0.050 g) and isopropyl ether (0.250 ml) was added(S)-(−)-1-phenylethylamine (0.020 ml), and the mixture was stirred atroom temperature overnight. This suspension was filtered to give a solid(0.060 g). The solid was added as a seed crystal to a mixture of4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid(0.050 g), (S)-(−)-1-phenylethylamine (0.020 ml) and ethyl acetate(0.250 ml), which had been stirred overnight at room temperature inadvance, and the mixture was further stirred at room temperatureovernight. The resulting suspension was filtered, and the obtained solidwas washed with ethyl acetate. The solid was dried under reducedpressure to give the title compound (0.019 g). The solid was analyzedunder HPLC analysis condition 4 to find that an isomer with a longretention time was the main component.

-   isomer with short retention time (retention time 20.09 min)-   isomer with long retention time (retention time 21.19 min)    Step 1-2

Under an argon atmosphere, (S)-(−)-1-phenylethylamine (0.392 ml) and aseed crystal of a salt of an optically active form of4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and(S)-(−)-1-phenylethylamine were added to a mixture of4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid(1.000 g) and ethyl acetate (5 ml), and the mixture was stirred at roomtemperature for 3 days. This suspension was filtered, and the obtainedsolid was washed with ethyl acetate (3 ml). The solid was dried underreduced pressure to give the title compound (0.466 g). The solid wasanalyzed under HPLC analysis condition 4 to find that an isomer with along retention time was the main component.

-   isomer with short retention time (retention time 19.91 min)-   isomer with long retention time (retention time 21.00 min)

Using this salt as an intermediate, compound Nos. 647, 657, 664 and 665were synthesized.

Example 12 Synthesis of(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-hydroxymethyl-propane-1,3-diol(compound No. 703)

Step 1

optically active form of2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionicacid

To a solution of an optically active form (33.3 g) oft-butyl[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetateand paraformaldehyde (18.3 g) in dimethylformamide (100 ml) was added atroom temperature a 1M solution (244 ml) of tetrabutylammonium fluoridein tetrahydrofuran, and the mixture was stirred at 90° C. for 4 hr. Tothe reaction mixture was added 1N hydrochloric acid (400 ml), and themixture was extracted with ethyl acetate (200 ml). The separated aqueouslayer was extracted twice with ethyl acetate (100 ml). The combinedorganic layer was successively washed once with 1N hydrochloric acid(100 ml), twice with brine (water/saturated brine=100 m1/10 ml) and oncewith saturated brine (100 ml), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The obtained residue was azeotropedtwice with toluene to give the title compound (28.3 g).

¹H-NMR (DMSO-D₆) δ: 13.13 (1H, br s), 8.12 (1H, d, J=0.7 Hz), 7.73 (1H,d, J=0.5 Hz), 7.66-7.61 (1H, m), 7.48-7.45 (1H, m), 7.42-7.38 (2H, m),7.36-7.31 (1H, m), 7.28-7.19 (2H, m), 5.15 (2H, br s), 4.24-4.07 (4H,m).

Step 2

(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-hydroxymethyl-propane-1,3-diol

To a solution of an optically active form (28.3 g) of2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionicacid in tetrahydrofuran (40 ml) were successively added dropwise at roomtemperature a 0.93M solution (225 ml) of borane-tetrahydrofuran complexin tetrahydrofuran and a 1.09M solution (32 ml) ofborane-tetrahydrofuran complex in tetrahydrofuran, and the mixture wasstirred for 3 hr. To the reaction mixture, ethanol (57 ml) was addeddropwise at room temperature and the mixture was stirred at 80° C. for 1hr. To this mixture were added water (150 ml) and saturated aqueoussodium hydrogen carbonate (100 ml), and the mixture was extracted twicewith ethyl acetate (100 ml, 50 ml). The combined organic layer wassuccessively washed twice with water (100 ml) and once with saturatedbrine (100 ml), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. A solution of the obtained residue in ethanol(50 ml) was cooled to 0° C., sodium borohydride (2.3 g) was addedthereto, and the mixture was stirred at room temperature for 2 hr. Tothe reaction mixture was added 1N hydrochloric acid (100 ml), and themixture was extracted with ethyl acetate (100 ml). The separated aqueouslayer was extracted again with ethyl acetate (50 ml). The combinedorganic layer was successively washed with water (100 ml), saturatedaqueous sodium hydrogen carbonate (100 ml) and saturated brine (100 ml),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=20/1 to 9/1) to give thetitle compound (21.6 g).

[α]D=+71.5° (25° C., c=1.000, methanol)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J=0.7 Hz), 7.70 (1H, d, J=0.7 Hz),7.65-7.61 (1H, m), 7.51-7.47 (1H, m), 7.40-7.36 (2H, m), 7.35-7.30 (1H,m), 7.29-7.24 (1H, m), 7.21-7.17 (1H, m), 4.83 (3H, t, J=5.4 Hz), 3.90(6H, d, J=5.6 Hz).

Example 13 Synthesis of(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-methyl-propane-1,3-diol(compound No. 673)

Step 1

2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionicacid ethyl ester

To a suspension of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g)and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added2-bromo-propionic acid ethyl ester (13 ml) and the mixture was stirredat 80° C. for 14 hr. The reaction mixture was cooled to 0° C., andtoluene (100 ml) and water (150 ml) were successively added dropwise.The mixture was partitioned, and the aqueous layer was extracted withtoluene (50 ml). The combined organic layer was successively washed oncewith 10% aqueous potassium carbonate (50 ml), twice with water (50 ml)and once with saturated brine (50 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give the titlecompound (21.6 g).

¹H-NMR (CDCl₃) δ: 7.85 (1H, s), 7.81 (1H, s), 5.10 (1H, q, J=7.3 Hz),4.19 (2H, q, J=7.1 Hz), 1.78 (3H, d, J=7.4 Hz), 1.32 (12H, s), 1.25 (3H,t, J=7.2 Hz).

Step 2

optically active form of2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionicacid ethyl ester

To a suspension of2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionicacid ethyl ester (29.2 g),(+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (20.4 g), andsodium hydrogen carbonate (11.1 g) in toluene/water (200 ml/66 ml) wereadded palladium acetate (743 mg) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.72 g) at roomtemperature, and the mixture was stirred at 115° C. for 8 hr. To thereaction mixture were added activated carbon (10 g) and Celite (10 g) atroom temperature and the mixture was stirred for 1 hr. The mixture wasfiltered through celite, and the solid was washed with toluene (100 ml).The filtrate was partitioned, and the aqueous layer was extracted withtoluene (60 ml). The combined organic layer was washed 3 times withwater (100 ml), and once with saturated brine (100 ml), dried overanhydrous sodium sulfate and concentrated under reduced pressure. To asolution of the obtained residue in toluene/ethyl acetate (3/1, 130 ml)was added silica gel (40 g), and the mixture was stirred at roomtemperature for 1 hr. The mixture was filtered, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=5/1 to 2/1) to give thetitle compound (27.9 g).

¹H-NMR (DMSO-D₆) δ: 8.20-8.18 (1H, m), 7.72-7.71 (1H, m), 7.67-7.63 (1H,m), 7.44-7.40 (2H, m), 7.37-7.23 (4H, m), 5.40-5.34 (1H, m), 4.22-4.15(2H, m), 1.78-1.75 (3H, m), 1.23-1.18 (3H, m).

Step 3

optically active form of2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionicacid

To a solution of an optically active form (27.9 g) of2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionicacid ethyl ester and paraformaldehyde (17.0 g) in dimethylformamide (100ml) was added at room temperature a 1M solution (170 ml) oftetrabutylammonium fluoride in tetrahydrofuran, and the mixture wasstirred at 100° C. for 6 hr. The reaction mixture was filtered throughcelite, and the solid was washed with ethyl acetate (100 ml). To thefiltrate was added 1N hydrochloric acid (400 ml), and the mixture wasextracted with ethyl acetate (100 ml). The separated aqueous layer wasextracted twice with ethyl acetate (100 ml). The combined organic layerwas successively washed once with 1N hydrochloric acid (100 ml), twicewith brine (water/saturated brine=100 ml/10 ml) and once with saturatedbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The obtained residue was azeotroped twice with tolueneto give the title compound (26.6 g).

¹H-NMR (DMSO-D₆) δ: 8.19-8.17 (1H, m), 7.71-7.70 (1H, m), 7.66-7.61 (1H,m), 7.46-7.19 (7H, m), 5.35-5.22 (1H, m), 4.21-4.12 (1H, m), 3.96-3.88(1H, m), 1.80 (3H, s).

Step 4

(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-methyl-propane-1,3-diol

To a solution of an optically active form (26.6 g) of2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionicacid in tetrahydrofuran (40 ml) was added dropwise at room temperature a1.09M solution (200 ml) of borane-tetrahydrofuran complex intetrahydrofuran, and the mixture was stirred for 3 hr. To the reactionmixture was added dropwise ethanol (25 ml) at room temperature and themixture was stirred at 80° C. for 1 hr. To this mixture were added water(200 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) andthe mixture was extracted twice with ethyl acetate (100 ml). Thecombined organic layer was successively washed twice with water (100 ml)and once with saturated brine (100 ml), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (eluent:chloroform/methanol=20/1 to 10/1) to give the title compound (17.4 g).

[α]D=+72.4° (25° C., c=1.004, methanol)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J=0.7 Hz), 7.68 (1H, d, J=0.7 Hz),7.65-7.62 (1H, m), 7.44-7.42 (1H, m), 7.40-7.36 (2H, m), 7.35-7.26 (2H,m), 7.21-7.17 (1H, m), 4.98-4.93 (2H, m), 3.84-3.79 (2H, m), 3.76-3.70(2H, m), 1.52 (3H, s).

Example 14 Synthesis of(+)-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol(compound No. 707)

Step 1

optically active form of[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-aceticacid t-butyl ester

To a suspension of t-butyl[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetate(24.8 g), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (20.0g), and sodium hydrogen carbonate (11.3 g) in toluene/water (200 ml/60ml) were added palladium acetate (750 mg) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.75 g) at roomtemperature and the mixture was stirred at 110° C. for 2 hr. To thereaction mixture were added water (80 ml) and activated carbon (2.0 g)at room temperature and the mixture was stirred for 1 hr. The mixturewas filtered through celite, and the solid was washed withtetrahydrofuran (100 ml). The filtrate was partitioned and the aqueouslayer was extracted with ethyl acetate (100 ml). The combined organiclayer was successively washed twice with water (100 ml) and once withsaturated brine (100 ml), anhydrous sodium sulfate and silica gel (40 g)were added, and the mixture was stirred overnight. The mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theobtained residue was treated with n-hexane/ethyl acetate (2/1, 120 ml)solution, and the resulting slurry was filtered to give the titlecompound (17.8 g).

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.65 (1H, d, J=0.7 Hz), 7.60 (1H,d, J=0.7 Hz), 7.51-7.49 (1H, m), 7.40-7.37 (1H, m), 7.28-7.23 (2H, m),7.14-7.13 (1H, m), 4.93 (1H, d, J=17.4 Hz), 4.88 (1H, d, J=17.4 Hz),4.80 (1H, s), 2.42 (3H, s), 1.52 (9H, s).

Step 2

optically active form of3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionicacid

To a solution of an optically active form (17.8 g) oft-butyl[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetateand paraformaldehyde (12.0 g) in dimethylformamide (60 ml) was added atroom temperature a 1M solution (120 ml) of tetrabutylammonium fluoridein tetrahydrofuran, and the mixture was stirred at 95° C. for 3 hr. Tothe reaction mixture were added 1N hydrochloric acid (180 ml) and water(90 ml), and the mixture was extracted with ethyl acetate (180 ml). Theseparated aqueous layer was extracted twice with ethyl acetate (90 ml).The combined organic layer was successively washed once with 1Nhydrochloric acid (90 ml), twice with water (90 ml) and once withsaturated brine (90 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound (15.5 g).

¹H-NMR (DMSO-D₆) δ: 13.10 (1H, br s), 8.03 (1H, s), 7.65 (1H, s),7.63-7.59 (1H, m), 7.44-7.40 (2H, m), 7.31-7.27 (1H, m), 7.25-7.20 (1H,m), 7.15 (2H, s), 5.14 (2H, br s), 4.21-4.09 (4H, m), 2.39 (3H, s).

Step 3

(+)-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol

To a solution of an optically active form (15.5 g) of3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionicacid in tetrahydrofuran (31 ml) was added dropwise at room temperature a1.09M solution (127 ml) of borane-tetrahydrofuran complex intetrahydrofuran, and the mixture was stirred for 5 hr. To the reactionmixture was added dropwise ethanol (15 ml) at room temperature and themixture was stirred at 75° C. for 1 hr. To this mixture were added water(90 ml) and saturated aqueous sodium hydrogen carbonate (150 ml), andthe mixture was extracted twice with ethyl acetate (150 ml, 75 ml). Thecombined organic layer was successively washed once with saturatedaqueous sodium hydrogen carbonate (75 ml), twice with water (75 ml) andonce with saturated brine (75 ml), dried over anhydrous sodium sulfateand concentrated under reduced pressure. To a solution of the obtainedresidue in ethanol (45 ml) was added sodium borohydride (1.3 g) at roomtemperature, and the mixture was stirred for 1 hr. To the reactionmixture was added 1N hydrochloric acid (150 ml), and the mixture wasextracted with ethyl acetate (150 ml). The separated aqueous layer wasextracted again with ethyl acetate (75 ml). The combined organic layerwas successively washed with water (75 ml), saturated aqueous sodiumhydrogen carbonate (75 ml), water (75 ml) and saturated brine (75 ml),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=20/1 to 10/1) to give thetitle compound (12.6 g).

[α]D=+65.6° (25° C., c=1.008, methanol)

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J=0.7 Hz), 7.63-7.59 (1H, m), 7.62 (1H,d, J=0.7 Hz), 7.46-7.40 (2H, m), 7.31-7.21 (2H, m), 7.14 (2H, s), 4.82(3H, t, J=5.6 Hz), 3.91 (6H, d, J=5.6 Hz), 2.39 (3H, s).

In the same manner as in the above-mentioned Examples, the compound Nos.1 to 707 including the compounds shown in the above-mentioned Exampleswere obtained. The structural formulas and ¹H-NMR spectrum data of theobtained compounds are shown in Table 1-1 to Table 1-106.

In the Tables, optically active compounds are indicated with (opticallyactive form) under compound No. Among them, those measured for opticalrotation are marked with (+) or (−) in the structural formulas.

¹H-NMR spectrum was measured in CDCl₃ or DMSO-D₆ using tetramethylsilaneas an internal standard, and all δ values are shown in ppm.

The symbols in the Tables mean the following.

-   s: singlet-   d: doublet-   t: triplet-   q: quartet-   dd: double doublet-   ddd: double double doublet-   brs: broad singlet-   m: multiplet-   J: coupling constant

TABLE 1-1 compound No. structural formula NMR 1

¹H-NMR (DMSO-D₆) δ: 8.65 (1H, dd, J = 5.1, 1.6 Hz), 8.04- 8.01 (1H, m),7.92-7.90 (1H, m), 7.75-7.72 (1H, m), 7.63- 7.59 (1H, m), 7.57-7.52 (1H,m), 7.50 (1H, s), 7.39 (1H, dd, J = 7.7, 4.9 Hz). 2

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.7 Hz), 7.70-7.66 (1H, m),7.55-7.49 (2H, m), 7.42- 7.38 (1H, m), 7.32-7.27 (2H, m), 7.17 (1H, s),2.64 (3H, s). 3

¹H-NMR (DMSO-D₆) δ: 7.79 (1H, d, J = 7.5 Hz), 7.73 (1H, d, J = 7.7 Hz),7.63-7.59 (1H, m), 7.50-7.44 (2H, m), 7.37-7.30 (2H, m), 7.17 (1H, s),2.39 (3H, s). 4

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, dd, J = 8.4, 5.1 Hz), 7.86 (1H, d, J = 7.5Hz), 7.66-7.62 (1H, m), 7.54-7.49 (1H, m), 7.44-7.34 (4H, m). 5

¹H-NMR (CDCl₃) δ: 7.71-7.67 (2H, m), 7.65-7.63 (1H, m), 7.59 (1H, d, J =7.9 Hz), 7.51-7.44 (2H, m), 7.40-7.36 (1H, m), 2.71 (1H, s). 6

¹H-NMR (CDCl₃) δ: 8.34 (1H, d, J = 7.7 Hz), 7.75-7.71 (1H, m), 7.65-7.61(1H, m), 7.55- 7.51 (1H, m), 7.46-7.40 (2H, m), 7.32-7.27 (1H, m), 2.71(1H, br s). 7

¹H-NMR (CDCl₃) δ: 7.86-7.83 (1H, m), 7.72-7.61 (3H, m), 7.56-7.48 (2H,m), 7.43-7.38 (1H, m), 2.73 (1H, s).

TABLE 1-2 compound No. structural formula NMR 8

¹H-NMR (CDCl₃) δ: 7.74-7.71 (1H, m), 7.66-7.63 (1H, m), 7.60-7.57 (1H,m), 7.51-7.46 (1H, m), 7.43-7.37 (2H, m), 7.29-7.26 (1H, m), 3.73 (1H,s). 9

¹H-NMR (CDCl₃) δ: 7.72-7.68 (1H, m), 7.65-7.60 (3H, m), 7.52-7.47 (1H,m), 7.42-7.37 (1H, m), 7.33 (1H, dd, J = 8.1, 1.9 Hz), 2.69 (1H, s). 10

¹H-NMR (DMSO-D₆) δ: 7.81 (1H, d, J = 7.5 Hz), 7.68-7.66 (1H, m),7.64-7.60 (1H, m), 7.53-7.47 (2H, m), 7.39-7.35 (1H, m), 7.21-7.17 (1H,m), 7.15 (1H, s), 2.40 (3H, s). 11

¹H-NMR (DMSO-D₆) δ: 7.81-7.78 (1H, m), 7.71-7.68 (1H, m), 7.59-7.54 (1H,m), 7.53-7.50 (1H, m), 7.49-7.43 (2H, m), 7.44 (1H, s), 7.41-7.36 (1H,m). 12

¹H-NMR (DMSO-D₆) δ: 7.93-7.90 (1H, m), 7.79 (1H, dd, J = 9.0, 2.3 Hz),7.67-7.63 (2H, m), 7.56-7.52 (1H, m), 7.45- 7.41 (1H, m), 7.31 (1H, s),7.23-7.17 (1H, m). 13

¹H-NMR (DMSO-D₆) δ: 7.90 (1H, d, J = 7.4 Hz), 7.73 (1H, d, J = 7.7 Hz),7.68-7.65 (1H, m), 7.60-7.52 (2H, m), 7.46- 7.41 (1H, m), 7.40 (1H, s),7.21-7.15 (1H, m). 14

¹H-NMR (CDCl₃) δ: 7.67-7.65 (2H, m), 7.55 (2H, d, J = 8.1 Hz), 7.46 (2H,dd, J = 8.1, 2.1 Hz), 2.77 (1H, s).

TABLE 1-3 compound No. structural formula NMR 15

¹H-NMR (DMSO-D₆) δ: 8.67 (1H, dd, J = 5.1, 1.5 Hz), 8.03- 7.99 (1H, m),7.57-7.53 (1H, m), 7.43-7.34 (4H, m), 2.80 (3H, s). 16

¹H-NMR (DMSO-D₆) δ: 8.61 (1H, dd, J = 5.1, 1.3 Hz), 7.98 (1H, d, J = 7.5Hz), 7.78 (1H, d, J = 7.7 Hz), 7.56-7.53 (1H, m), 7.44-7.40 (2H, m),7.35 (1H, dd, J = 7.6, 5.0 Hz), 2.43 (3H, s). 17

¹H-NMR (CDCl₃) δ: 7.67 (1H, d, J = 7.9 Hz), 7.56-7.53 (2H, m), 7.30-7.27(1H, m), 7.24- 7.22 (2H, m), 2.66 (1H, br s), 2.64 (3H, s), 2.44 (3H,s). 18

¹H-NMR (CDCl₃) δ: 7.74 (1H, d, J = 7.7 Hz), 7.72-7.69 (1H, m), 7.49-7.44(1H, m), 7.38- 7.36 (1H, m), 7.34-7.30 (1H, m), 7.08-7.06 (1H, m), 2.66(1H, br s), 2.62 (3H, s), 2.39 (3H, s). 19

¹H-NMR (DMSO-D₆) δ: 9.95 (1H, br s), 7.77 (1H, d, J = 7.5 Hz), 7.67-7.62(1H, m), 7.54- 7.48 (2H, m), 7.42-7.35 (3H, m), 7.26 (1H, s), 2.17 (3H,br s). 20

¹H-NMR (DMSO-D₆) δ: 7.89 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m),7.50-7.45 (1H, m), 7.35- 7.31 (1H, m), 7.21-7.17 (1H, m), 7.15-7.07 (1H,m), 7.05- 6.98 (1H, m), 6.13 (3H, br s). 21

¹H-NMR (DMSO-D₆) δ: 8.28-8.25 (1H, m), 7.80 (1H, d, J = 1.8 Hz),7.74-7.71 (1H, m), 7.66- 7.64 (1H, m), 7.64-7.59 (1H, m), 7.61 (1H, s),7.55-7.51 (1H, m).

TABLE 1-4 compound No. structural formula NMR 22

¹H-NMR (DMSO-D₆) δ: 10.14 (1H, br s), 7.97-7.96 (1H, m), 7.77-7.74 (2H,m), 7.71-7.68 (1H, m), 7.62-7.59 (1H, m), 7.49-7.45 (1H, m), 7.34-7.30(1H, m), 7.22 (1H, s), 2.07 (3H, s). 23

¹H-NMR (DMSO-D₆) δ: 8.20-8.18 (1H, m), 8.14 (1H, dd, J = 8.0, 1.5 Hz),8.03 (1H, d, J = 7.7 Hz), 8.00-7.97 (1H, m), 7.72-7.68 (1H, m),7.60-7.56 (1H, m), 7.51-7.47 (1H, m), 7.48 (1H, s), 3.90 (3H, s). 24

¹H-NMR (DMSO-D₆) δ: 13.18 (1H, br s), 8.19-8.17 (1H, m), 8.11 (1H, dd, J= 8.0, 1.5 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.98-7.95 (1H, m), 7.71-7.68(1H, m), 7.59-7.55 (1H, m), 7.50-7.45 (1H, m), 7.43 (1H, s). 25

¹H-NMR (DMSO-D₆) δ: 7.83 (1H, d, J = 7.7 Hz), 7.70-7.66 (1H, m),7.56-7.49 (2H, m), 7.42- 7.37 (1H, m), 7.33 (2H, d, J = 4.9 Hz), 7.16(1H, s), 3.09- 2.95 (2H, m), 1.28 (3H, t, J = 7.5 Hz). 26

¹H-NMR (DMSO-D₆) δ: 7.62 (1H, d, J = 7.5 Hz), 7.57-7.54 (1H, m),7.47-7.41 (1H, m), 7.34- 7.29 (1H, m), 7.28-7.24 (1H, m), 6.92 (1H, d, J= 2.0 Hz), 6.83 (1H, s), 6.53 (1H, dd, J = 8.3, 2.1 Hz), 5.44 (2H, brs). 27

¹H-NMR (DMSO-D₆) δ: 8.07-8.04 (1H, m), 7.88-7.82 (2H, m), 7.72-7.68 (1H,m), 7.55-7.44 (3H, m), 7.36 (1H, s), 3.97 (3H, s). 28

¹H-NMR (DMSO-D₆) δ: 10.17 (1H, br s), 8.06 (1H, d, J = 1.6 Hz),7.73-7.70 (1H, m), 7.64- 7.61 (1H, m), 7.57-7.53 (1H, m), 7.53-7.47 (2H,m), 7.41- 7.37 (1H, m), 7.16 (1H, s), 2.09 (3H, s).

TABLE 1-5 compound No. structural formula NMR 29

¹H-NMR (DMSO-D₆) δ: 8.18-8.16 (1H, m), 8.12 (1H, br s), 8.05 (1H, dd, J= 8.0, 1.5 Hz), 7.96-7.92 (2H, m), 7.69-7.66 (1H, m), 7.57-7.53 (1H, m),7.47-7.42 (2H, m), 7.35 (1H, s). 30

¹H-NMR (DMSO-D₆) δ: 8.63-8.55 (1H, m), 8.15-8.11 (1H, m), 8.00 (1H, dd,J = 7.9, 1.6 Hz), 7.96-7.91 (2H, m), 7.69- 7.66 (1H, m), 7.57-7.52 (1H,m), 7.46-7.42 (1H, m), 7.36 (1H, s), 2.81 (3H, d, J = 4.6 Hz). 31

¹H-NMR (DMSO-D₆) δ: 7.94-7.91 (2H, m), 7.68-7.65 (1H, m), 7.63-7.62 (1H,m), 7.58-7.52 (2H, m), 7.46-7.41 (1H, m), 7.37 (1H, s), 3.00 (3H, br s),2.96 (3H, br s). 32

¹H-NMR (DMSO-D₆) δ: 13.52 (1H, br s), 8.23 (1H, d, J = 7.5 Hz),7.84-7.80 (2H, m), 7.71- 7.67 (1H, m), 7.54-7.42 (3H, m), 7.31 (1H, brs). 33

¹H-NMR (DMSO-D₆) δ: 8.11 (1H, br s), 7.94 (1H, d, J = 7.7 Hz), 7.72-7.64(3H, m), 7.50- 7.38 (4H, m), 7.28 (1H, s). 34

¹H-NMR (DMSO-D₆) δ: 8.62-8.54 (1H, m), 7.77-7.74 (1H, m), 7.72-7.69 (1H,m), 7.68-7.64 (1H, m), 7.50-7.38 (4H, m), 7.29 (1H, s), 2.86 (3H, d, J =4.4 Hz). 35

¹H-NMR (DMSO-D₆) δ: 7.71-7.66 (2H, m), 7.53-7.34 (5H, m), 7.33 (1H, brs), 3.14 (3H, s), 2.76 (3H, s).

TABLE 1-6 compound No. structural formula NMR 36

¹H-NMR (DMSO-D₆) δ: 8.73 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 1.5 Hz),7.93-7.89 (1H, m), 7.76-7.73 (1H, m), 7.67-7.56 (2H, m), 7.66 (1H, s).37

¹H-NMR (DMSO-D₆) δ: 7.78-7.73 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44 (1H,m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.17- 7.15 (1H, m), 7.07 (1H, dd, J= 8.3, 2.6 Hz), 3.83 (3H, s). 38

¹H-NMR (DMSO-D₆) δ: 9.82 (1H, s), 7.67 (1H, d, J = 7.4 Hz), 7.63 (1H, d,J = 8.3 Hz), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m),7.15 (1H, s), 7.07-7.04 (1H, m), 6.87 (1H, dd, J = 8.1, 2.3 Hz). 39

¹H-NMR (DMSO-D₆) δ: 7.80 (1H, d, J = 7.4 Hz), 7.75 (1H, d, J = 7.7 Hz),7.63-7.59 (1H, m), 7.50-7.46 (2H, m), 7.37-7.32 (2H, m), 7.19 (1H, s),2.69 (2H, q, J = 7.6 Hz), 1.22 (3H, t, J = 7.5 Hz). 40

¹H-NMR (DMSO-D₆) δ: 8.41 (1H, d, J = 0.9 Hz), 8.05-7.99 (2H, m),7.81-7.77 (1H, m), 7.70- 7.66 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H,m), 7.44 (1H, s), 3.92 (3H, s). 41

¹H-NMR (DMSO-D₆) δ: 13.23 (1H, br s), 8.38 (1H, d, J = 0.9 Hz),8.02-7.97 (2H, m), 7.78- 7.74 (1H, m), 7.69-7.65 (1H, m), 7.57-7.52 (1H,m), 7.46- 7.41 (1H, m), 7.41 (1H, s). 42

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 1.1 Hz), 8.08 (1H, br s), 7.90-7.86(2H, m), 7.71- 7.65 (2H, m), 7.57-7.53 (1H, m), 7.51 (1H, br s),7.45-7.41 (1H, m), 7.35 (1H, s).

TABLE 1-7 compound No. structural formula NMR 43

¹H-NMR (DMSO-D₆) δ: 8.59-8.53 (1H, m), 8.26 (1H, d, J = 1.1 Hz), 7.89(1H, d, J = 7.5 Hz), 7.82 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.69 (1H, m),7.68- 7.65 (1H, m), 7.58-7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s),2.83 (3H, d, J = 4.6 Hz). 44

¹H-NMR (DMSO-D₆) δ: 7.96-7.91 (2H, m), 7.69-7.64 (2H, m), 7.55-7.50 (1H,m), 7.44-7.37 (2H, m), 7.33 (1H, s), 3.03 (3H, br s), 2.94 (3H, br s).45

¹H-NMR (DMSO-D₆) δ: 8.07-8.04 (1H, m), 7.98-7.94 (2H, m), 7.76-7.71 (1H,m), 7.62-7.57 (1H, m), 7.52-7.47 (1H, m), 7.41 (1H, s), 3.89 (3H, s),2.71 (3H, s). 46

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m),7.50-7.45 (1H, m), 7.40- 7.32 (2H, m), 7.27-7.23 (1H, m), 7.20 (1H, s),7.17 (1H, d, J = 8.4 Hz), 3.98 (3H, s). 47

¹H-NMR (DMSO-D₆) δ: 7.87 (1H, d, J = 7.5 Hz), 7.63-7.59 (1H, m),7.54-7.47 (2H, m), 7.46 (1H, d, J = 2.4 Hz), 7.40-7.35 (1H, m), 7.10(1H, s), 6.92 (1H, dd, J = 8.4, 2.4 Hz), 3.85 (3H, s). 48

¹H-NMR (CDCl₃) δ: 8.29 (1H, d, J = 7.9 Hz), 7.91-7.84 (2H, m), 7.75-7.70(1H, m), 7.50- 7.45 (1H, m), 7.42-7.38 (2H, m), 4.48 (2H, q, J = 7.1Hz), 2.72 (1H, s), 1.45 (3H, t, J = 7.2 Hz). 49

¹H-NMR (DMSO-D₆) δ: 8.23-8.19 (1H, m), 7.98 (2H, d, J = 7.9 Hz),7.79-7.75 (1H, m), 7.71- 7.66 (1H, m), 7.63-7.54 (2H, m), 7.55 (1H, s).

TABLE 1-8 compound No. structural formula NMR 50

¹H-NMR (CDCl₃) δ: 8.54 (1H, d, J = 1.5 Hz), 8.45 (1H, br s), 8.37-8.33(1H, m), 7.79-7.74 (1H, m), 7.54-7.44 (2H, m), 4.03 (3H, s), 3.96 (3H,s), 3.03 (0H, s). 51

¹H-NMR (CDCl₃) δ: 7.76-7.72 (1H, m), 7.68-7.65 (1H, m), 7.64-7.61 (1H,m), 7.59 (1H, d, J = 7.7 Hz), 7.52-7.47 (1H, m), 7.42-7.34 (2H, m), 3.97(1H, br s), 3.53 (1H, br s), 3.26 (1H, br s), 3.03-2.91 (3H, m),1.26-1.10 (3H, m). 52

¹H-NMR (CDCl₃) δ: 7.75-7.72 (1H, m), 7.68-7.65 (1H, m), 7.63-7.61 (1H,m), 7.60 (1H, d, J = 7.7 Hz), 7.52-7.47 (1H, m), 7.42-7.36 (2H, m), 3.87(1H, s), 3.75-3.22 (4H, m), 1.73-1.43 (6H, m). 53

¹H-NMR (CDCl₃) δ: 7.77-7.72 (2H, m), 7.69-7.65 (1H, m), 7.60-7.57 (1H,m), 7.52-7.47 (2H, m), 7.43-7.38 (1H, m), 4.36 (1H, br s), 3.62-3.35(4H, m), 1.98-1.80 (4H, m). 54

¹H-NMR (CDCl₃) δ: 7.76-7.72 (1H, m), 7.68-7.65 (1H, m), 7.63-7.57 (2H,m), 7.52-7.47 (1H, m), 7.42-7.37 (1H, m), 7.36-7.32 (1H, m), 3.93 (1H,br s), 3.50 (2H, br s), 3.25 (2H, br s), 1.22 (3H, br s), 1.12 (3H, brs). 55

¹H-NMR (DMSO-D₆) δ: 7.84 (1H, d, J = 8.1 Hz), 7.81 (1H, d, J = 7.4 Hz),7.65-7.61 (1H, m), 7.53-7.48 (1H, m), 7.46- 7.43 (1H, m), 7.39-7.34 (1H,m), 7.31-7.27 (1H, m). 56

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.61-7.58 (1H, m), 7.53-7.42 (4H,m), 7.37-7.33 (1H, m), 7.25-7.20 (2H, m), 7.17-7.12 (1H, m), 7.07-7.02(2H, m), 3.50 (3H, s), 2.84 (1H, br s).

TABLE 1-9 compound No. structural formula NMR 57

¹H-NMR (CDCl₃) δ: 7.76-7.72 (1H, m), 7.69-7.66 (1H, m), 7.65-7.60 (2H,m), 7.53-7.48 (1H, m), 7.43-7.37 (2H, m), 4.33-3.47 (1H, m), 3.13-2.80(3H, m), 2.33-1.93 (4H, m), 1.79-1.37 (2H, m). 58

¹H-NMR (CDCl₃) δ: 7.83-7.80 (1H, m), 7.78-7.73 (1H, m), 7.71-7.67 (2H,m), 7.66-7.62 (1H, m), 7.52-7.47 (1H, m), 7.43-7.39 (1H, m), 4.39-3.99(5H, m), 2.37-2.26 (2H, m). 59

¹H-NMR (DMSO-D₆) δ: 8.07 (1H, d, J = 7.7 Hz), 7.87-7.84 (1H, m), 7.83(1H, dd, J = 7.8, 1.0 Hz), 7.72-7.68 (1H, m), 7.54- 7.44 (3H, m), 7.36(1H, s), 4.36 (2H, t, J = 6.6 Hz), 1.83- 1.73 (2H, m), 0.99 (3H, t, J =7.4 Hz). 60

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, d, J = 7.4 Hz), 7.86-7.83 (1H, m), 7.79(1H, dd, J = 7.9, 1.2 Hz), 7.71-7.68 (1H, m), 7.55- 7.44 (3H, m), 7.35(1H, s), 5.33-5.23 (1H, m), 1.40 (3H, d, J = 3.7 Hz), 1.38 (3H, d, J =3.7 Hz). 61

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 7.4 Hz), 8.14-8.13 (1H, m), 8.09(1H, d, J = 1.4 Hz), 7.79-7.76 (1H, m), 7.68-7.64 (1H, m), 7.66 (1H, s),7.61- 7.57 (1H, m), 3.92 (3H, s). 62

¹H-NMR (DMSO-D₆) δ: 9.81 (1H, s), 7.74 (1H, d, J = 7.5 Hz), 7.61-7.57(1H, m), 7.49-7.44 (1H, m), 7.43-7.39 (1H, m), 7.38-7.33 (1H, m), 7.18(1H, d, J = 2.2 Hz), 6.99 (1H, s), 6.75 (1H, dd, J = 8.3, 2.3 Hz). 63

¹H-NMR (DMSO-D₆) δ: 10.27 (1H, s), 7.94 (1H, d, J = 7.4 Hz), 7.61-7.57(1H, m), 7.48-7.43 (1H, m), 7.33-7.28 (1H, m), 7.21-7.17 (1H, m),7.12-7.08 (2H, m), 6.94 (1H, dd, J = 8.1, 0.9 Hz).

TABLE 1-10 compound No. structural formula NMR 64

¹H-NMR (DMSO-D₆) δ: 8.00-7.97 (1H, m), 7.92-7.89 (2H, m), 7.78-7.75 (1H,m), 7.66-7.60 (2H, m), 7.56-7.52 (1H, m), 7.48 (1H, s). 65

¹H-NMR (DMSO-D₆) δ: 7.74-7.65 (2H, m), 7.53-7.39 (5H, m), 7.35 (1H, s),3.42 (3H, br s), 3.36 (3H, br s). 66

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m),7.51-7.46 (1H, m), 7.37- 7.32 (2H, m), 7.25-7.22 (1H, m), 7.18 (1H, s),7.14 (1H, d, J = 8.2 Hz), 4.23 (2H, q, J = 7.0 Hz), 1.48 (3H, t, J = 6.9Hz). 67

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.5 Hz), 7.62-7.59 (1H, m),7.53-7.47 (2H, m), 7.45 (1H, d, J = 2.4 Hz), 7.39-7.35 (1H, m), 7.08(1H, s), 6.90 (1H, dd, J = 8.4, 2.4 Hz), 4.13 (2H, q, J = 6.98 Hz), 1.37(3H, t, J = 6.9 Hz). 68

¹H-NMR (DMSO-D₆) δ: 7.89-7.79 (3H, m), 7.70-7.66 (1H, m), 7.54-7.40 (3H,m), 7.31 (1H, s), 2.71 (3H, s). 69

¹H-NMR (DMSO-D₆) δ: 7.82 (1H, d, J = 7.7 Hz), 7.79 (1H, d, J = 7.9 Hz),7.65-7.61 (2H, m), 7.52-7.47 (1H, m), 7.45- 7.41 (1H, m), 7.39-7.34 (1H,m), 7.21 (1H, s), 5.33 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.6 Hz). 70

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.64-7.60 (1H, m), 7.56 (1H, d, J =7.9 Hz), 7.52-7.50 (1H, m), 7.47-7.43 (1H, m), 7.34-7.27 (2H, m), 2.70(1H, br s), 2.69-2.63 (2H, m), 1.74-1.64 (2H, m), 0.97 (3H, t, J = 7.3Hz).

TABLE 1-11 compound No. structural formula NMR 71

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.64-7.61 (1H, m), 7.59-7.55 (2H,m), 7.48-7.43 (1H, m), 7.35-7.30 (2H, m), 3.05-2.93 (1H, m), 2.70 (1H,s), 1.31 (3H, d, J = 1.4 Hz), 1.29 (3H, d, J = 1.4 Hz). 72

¹H-NMR (DMSO-D₆) δ: 8.59-8.55 (1H, m), 8.26 (1H, d, J = 1.3 Hz), 7.90(1H, d, J = 7.5 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.65 (2H, m),7.57- 7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 3.37-3.29 (2H, m),1.16 (3H, t, J = 7.2 Hz). 73

¹H-NMR (DMSO-D₆) δ: 8.35-8.31 (1H, m), 8.27-8.25 (1H, m), 7.91 (1H, d, J= 7.5 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.65 (2H, m), 7.57-7.53(1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 4.17-4.08 (1H, m), 1.21 (3H,s), 1.19 (3H, s). 74

¹H-NMR (DMSO-D₆) δ: 7.83 (1H, d, J = 7.7 Hz), 7.69-7.65 (1H, m),7.58-7.50 (3H, m), 7.41- 7.35 (2H, m), 7.17 (1H, s), 5.43 (1H, t, J =5.4 Hz), 4.91-4.81 (2H, m). 75

¹H-NMR (DMSO-D₆) δ: 7.86-7.81 (2H, m), 7.66-7.62 (1H, m), 7.61-7.58 (1H,m), 7.53-7.48 (1H, m), 7.46-7.43 (1H, m), 7.40-7.36 (1H, m), 7.24 (1H,s), 4.49 (2H, s), 3.34 (3H, s). 76

¹H-NMR (DMSO-D₆) δ: 8.18-8.15 (2H, m), 8.05-7.98 (2H, m), 7.72-7.68 (1H,m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.44 (1H, s), 2.64 (3H, s). 77

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.4 Hz), 7.73-7.61 (3H, m),7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.39 (0.5H, s), 7.35 (0.5H, s),4.23-3.94 (1H, m), 3.60-3.47 (1H, m), 3.38- 3.29 (1H, m), 2.14-2.03 (1H,m), 1.97-1.82 (1H, m), 1.78- 1.66 (1H, m), 1.62-1.50 (1H, m), 1.33-1.20(2H, m), 0.95- 0.77 (1H, m).

TABLE 1-12 compound No. structural formula NMR 78

¹H-NMR (DMSO-D₆) δ: 8.13-8.11 (1H, m), 8.03-7.92 (3H, m), 7.69-7.66 (1H,m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.41 (1H, s), 4.48-4.42 (2H,m), 4.02-3.97 (2H, m). 79

¹H-NMR (DMSO-D₆) δ: 7.96-7.91 (2H, m), 7.87-7.85 (1H, m), 7.78-7.74 (1H,m), 7.69-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.43 (1H, m), 7.39 (1H,s), 5.76 (1H, d, J = 6.0 Hz), 4.56-4.43 (2H, m), 4.34-4.22 (1H, m),4.13-4.00 (1H, m), 3.89-3.71 (1H, m). 80

¹H-NMR (CDCl₃) δ: 7.64-7.60 (1H, m), 7.51-7.47 (2H, m), 7.42- 7.37 (1H,m), 7.23-7.18 (1H, m), 7.06-7.03 (1H, m), 6.76 (1H, dd, J = 8.5, 2.4Hz), 3.03 (6H, s), 2.69 (1H, br s). 81

¹H-NMR (DMSO-D₆) δ: 7.80-7.76 (2H, m), 7.69-7.66 (1H, m), 7.64-7.61 (1H,m), 7.52-7.40 (3H, m), 7.32 (1H, s), 3.16- 2.97 (2H, m), 1.17 (3H, t, J= 7.2 Hz). 82

¹H-NMR (DMSO-D₆) δ: 7.75 (1H, d, J = 7.7 Hz), 7.69-7.65 (1H, m),7.64-7.60 (1H, m), 7.56-7.48 (2H, m), 7.43-7.36 (2H, m), 7.22 (1H, s),4.79 (1H, d, J = 12.3 Hz), 4.74 (1H, d, J = 12.3 Hz), 3.40 (3H, s). 83

¹H-NMR (DMSO-D₆) δ: 7.83-7.78 (2H, m), 7.72-7.66 (2H, m), 7.55-7.51 (1H,m), 7.49-7.40 (2H, m), 7.33 (1H, s), 2.62-2.55 (1H, m), 1.26-1.14 (4H,m). 84

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (1H, m), 7.65-7.62 (1H, m), 7.54-7.49 (1H,m), 7.38-7.30 (3H, m), 7.23 (1H, dd, J = 7.1, 2.0 Hz), 7.13 (1H, s),2.76 (6H, s).

TABLE 1-13 compound No. structural formula NMR 85

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.7 Hz), 7.63-7.61 (1H, m),7.49-7.44 (1H, m), 7.33-7.24 (2H, m), 7.05-7.00 (1H, m), 6.82 (2H, brs), 6.67 (2H, s), 2.88 (3H, s). 86

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (2H, m), 7.90-7.87 (1H, m), 7.80- 7.76(1H, m), 7.70-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.40(1H, br s), 4.55-4.40 (1H, m), 4.32-4.23 (2H, m), 4.22- 4.11 (1H, m),3.97-3.78 (1H, m), 3.24 (3H, s). 87

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.9 Hz), 7.88-7.86 (1H, m),7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H,m), 7.40 (1H, s), 4.83 (1H, t, J = 5.3 Hz), 4.40-4.31 (1H, m), 4.10-4.03(2H, m), 3.84-3.78 (1H, m), 3.56 (2H, t, J = 5.7 Hz), 2.80-2.69 (1H, m).88

¹H-NMR (DMSO-D₆) δ: 8.14-8.11 (1H, m), 8.01-7.96 (1H, m), 7.92- 7.86(2H, m), 7.69-7.63 (1H, m), 7.57-7.50 (1H, m), 7.45-7.39 (1H, m), 7.32(1H, s), 4.41-4.33 (1H, m), 3.95-3.85 (1H, m), 3.65-3.54 (1H, m),3.19-3.07 (1H, m), 2.11- 1.94 (1H, m), 0.95 (3H, d, J = 6.4 Hz). 89

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.45-7.41 (1H,m), 7.30-7.23 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 4.10 (2H, q, J =7.0 Hz), 2.67 (1H, s), 1.44 (3H, t, J = 6.9 Hz). 90

¹H-NMR (DMSO-D₆) δ: 7.95-7.91 (2H, m), 7.87-7.71 (2H, m), 7.69- 7.65(1H, m), 7.57-7.52 (1H, m), 7.47-7.42 (1H, m), 7.40 (0.5H, s), 7.36(0.5H, s), 4.84-3.87 (3H, m), 2.46-2.31 (1H, m), 1.94- 1.74 (1H, m),1.55-1.35 (2H, m), 1.21-1.00 (1H, m). 91

¹H-NMR (DMSO-D₆) δ: 7.93-7.88 (1H, m), 7.74-7.68 (2H, m), 7.60- 7.54(2H, m), 7.48-7.43 (1H, m), 7.32 (1H, s), 4.39-4.29 (2H, m), 4.12-4.02(2H, m), 2.68 (3H, s), 2.34-2.23 (2H, m).

TABLE 1-14 compound No. structural formula NMR 92

¹H-NMR (DMSO-D₆) δ: 8.64 (1H, s), 7.79 (1H, d, J = 7.3 Hz), 7.72-7.68(1H, m), 7.59-7.56 (2H, m), 7.53-7.49 (1H, m), 7.44-7.40 (2H, m), 7.35(1H, s), 7.11-7.06 (1H, m). 93

¹H-NMR (DMSO-D₆) δ: 7.80-7.76 (1H, m), 7.75-7.71 (1H, m), 7.69-7.66 (1H,m), 7.52-7.39 (4H, m), 7.32 (1H, s), 3.50- 3.42 (1H, m), 1.18 (3H, d, J= 7.0 Hz), 1.13 (3H, d, J = 7.0 Hz). 94

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.7 Hz), 7.83-7.81 (1H, m),7.78-7.73 (2H, m), 7.65- 7.61 (1H, m), 7.58-7.52 (1H, m), 7.57 (1H, s),4.39-4.33 (2H, m), 4.11-4.04 (2H, m), 2.34-2.24 (2H, m). 95

¹H-NMR (DMSO-D₆) δ: 7.73-7.66 (2H, m), 7.59-7.54 (1H, m), 7.46-7.41 (1H,m), 7.29-7.23 (1H, m), 7.17 (1H, br s), 6.99 (1H, br s), 4.64 (2H, brs), 2.81 (3H, br s). 96

¹H-NMR (CDCl₃) δ: 7.74-7.65 (3H, m), 7.54-7.48 (2H, m), 7.43-7.37 (1H,m), 7.32-7.27 (1H, m), 3.29 (3H, br s), 3.10 (1H, br s), 1.91 (3H, brs). 97

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.9 Hz), 7.91 (1H, d, J = 7.4 Hz),7.89-7.87 (1H, m), 7.83 (1H, dd, J = 7.9, 1.6 Hz), 7.73-7.69 (2H, m),7.68- 7.64 (1H, m), 7.56-7.49 (3H, m), 7.44-7.38 (2H, m), 7.35 (1H, s).98

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, d, J = 7.9 Hz), 8.02-7.99 (2H, m), 7.92(1H, dd, J = 7.9, 1.6 Hz), 7.79-7.75 (2H, m), 7.74- 7.69 (2H, m),7.63-7.57 (3H, m), 7.52-7.47 (2H, m).

TABLE 1-15 compound No. structural formula NMR 99

¹H-NMR (DMSO-D₆) δ: 8.18-8.16 (1H, m), 8.09-8.00 (4H, m), 7.79-7.77 (1H,m), 7.73-7.70 (1H, m), 7.62-7.57 (1H, m), 7.52-7.47 (2H, m), 7.36-7.33(1H, m). 100

¹H-NMR (DMSO-D₆) δ: 10.09 (1H, s), 8.10-8.08 (1H, m), 7.71 (1H, d, J =7.4 Hz), 7.63-7.61 (1H, m), 7.57-7.47 (3H, m), 7.41-7.36 (1H, m), 7.14(1H, s), 2.37 (2H, q, J = 7.6 Hz), 1.11 (3H, t, J = 7.5 Hz). 101

¹H-NMR (DMSO-D₆) δ: 10.05 (1H, s), 8.12 (1H, d, J = 7.7 Hz), 7.63 (1H,d, J = 7.4 Hz), 7.57-7.48 (3H, m), 7.41-7.37 (1H, m), 7.15 (1H, s),2.69-2.58 (1H, m), 1.13 (6H, d, J = 6.7 Hz). 102

¹H-NMR (CDCl₃) δ: 8.61 (1H, d, J = 2.3 Hz), 8.44-8.42 (1H, m), 7.89-7.85(2H, m), 7.77 (1H, d, J = 13.9 Hz), 7.72 (1H, d, J = 7.9 Hz), 7.69 (1H,d, J = 7.7 Hz), 7.60-7.57 (1H, m), 7.53-7.49 (1H, m), 7.43-7.38 (1H, m),7.33 (1H, dd, J = 8.0, 4.8 Hz), 4.49 (1H, br s). 103

¹H-NMR (CDCl₃) δ: 8.58-8.55 (2H, m), 7.87-7.85 (1H, m), 7.78-7.69 (4H,m), 7.54-7.47 (3H, m), 7.43-7.38 (1H, m), 4.19 (1H, br s). 104

¹H-NMR (DMSO-D₆) δ: 7.96-7.90 (2H, m), 7.87 (1H, s), 7.79- 7.74 (1H, m),7.69-7.64 (1H, m), 7.57-7.52 (1H, m), 7.47- 7.41 (1H, m), 7.38 (1H, s),4.52-4.43 (1H, m), 4.37-4.23 (2H, m), 4.21-4.11 (1H, m), 3.89-3.82 (1H,m), 3.42 (2H, q, J = 6.9 Hz), 1.13 (3H, t, J = 7.0 Hz). 105

¹H-NMR (DMSO-D₆) δ: 7.97-7.91 (2H, m), 7.88 (1H, s), 7.80- 7.76 (1H, m),7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47- 7.42 (1H, m), 7.39 (1H, brs), 4.54-4.43 (1H, m), 4.37-4.24 (2H, m), 4.22-4.12 (1H, m), 3.90-3.83(1H, m), 3.36-3.27 (2H, m), 1.58-1.48 (2H, m), 0.88 (3H, t, J = 7.4 Hz).

TABLE 1-16 compound No. structural formula NMR 106

¹H-NMR (DMSO-D₆) δ: 7.97-7.91 (2H, m), 7.90-7.86 (1H, m), 7.80-7.76 (1H,m), 7.69-7.65 (1H, m), 7.58-7.52 (1H, m), 7.48-7.42 (1H, m), 7.39 (1H,br s), 4.53-4.42 (1H, m), 4.41-4.34 (1H, m), 4.32-4.24 (1H, m),4.21-4.12 (1H, m), 3.92-3.82 (1H, m), 3.55-3.49 (2H, m), 3.48-3.43 (2H,m), 3.25 (3H, s). 107

¹H-NMR (DMSO-D₆) δ: 12.73 (1H, br s), 7.97-7.92 (2H, m), 7.89-7.86 (1H,m), 7.80-7.75 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.42(1H, m), 7.40 (1H, br s), 4.53-4.42 (2H, m), 4.33-4.19 (2H, m), 4.07(2H, s), 3.98- 3.90 (1H, m). 108

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (2H, m), 7.89-7.86 (1H, m), 7.79-7.76 (1H,m), 7.70-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.40 (1H,s), 4.67 (1H, t, J = 5.3 Hz), 4.54-4.45 (1H, m), 4.41-4.35 (1H, m),4.32-4.24 (1H, m), 4.21-4.13 (1H, m), 3.94-3.84 (1H, m), 3.53-3.48 (2H,m), 3.45-3.40 (2H, m). 109

¹H-NMR (DMSO-D₆) δ: 8.21-8.17 (2H, m), 8.02 (1H, d, J = 8.3 Hz),8.00-7.97 (1H, m), 7.71- 7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H,m), 7.43 (1H, s), 3.92-3.83 (1H, m), 1.99-1.88 (2H, m), 1.84-1.70 (2H,m), 1.66-1.61 (4H, m). 110

¹H-NMR (DMSO-D₆) δ: 7.73 (2H, d, J = 8.1 Hz), 7.60-7.56 (1H, m),7.47-7.43 (1H, m), 7.31- 7.27 (1H, m), 7.21 (1H, s), 7.14-7.11 (1H, m),7.04 (1H, dd, J = 8.3, 2.3 Hz), 4.71- 4.61 (1H, m), 1.31 (3H, d, J = 4.6Hz), 1.29 (3H, d, J = 4.4 Hz). 111

¹H-NMR (DMSO-D₆) δ: 8.20 (1H, d, J = 7.9 Hz), 7.81-7.78 (1H, m),7.74-7.71 (1H, m), 7.70- 7.66 (1H, m), 7.52-7.41 (3H, m), 7.32 (1H, s),4.55-4.49 (2H, m), 4.16-4.10 (2H, m). 112

¹H-NMR (CDCl₃) δ: 8.54-8.52 (1H, m), 8.18-8.16 (1H, m), 8.04 (1H, dd, J= 7.9, 1.8 Hz), 7.77-7.64 (4H, m), 7.61- 7.58 (1H, m), 7.47-7.43 (1H,m), 7.39-7.35 (1H, m), 7.17- 7.13 (1H, m), 4.05 (1H, br s).

TABLE 1-17 compound No. structural formula NMR 113

¹H-NMR (DMSO-D₆) δ: 8.45 (1H, d, J = 7.7 Hz), 7.76-7.67 (3H, m),7.63-7.58 (1H, m), 7.53-7.48 (1H, m), 7.40 (1H, br s), 7.37-7.33 (1H,m). 114

¹H-NMR (DMSO-D₆) δ: 8.50-8.47 (1H, m), 7.91 (1H, d, J = 1.3 Hz),7.87-7.84 (1H, m), 7.76-7.73 (1H, m), 7.67-7.62 (1H, m), 7.58-7.53 (1H,m), 7.55 (1H, s), 4.41-4.30 (2H, m), 4.14-4.02 (2H, m), 2.34- 2.23 (2H,m). 115

¹H-NMR (CDCl₃) δ: 7.78-7.64 (3H, m), 7.61-7.57 (2H, m), 7.51-7.46 (1H,m), 7.44-7.38 (1H, m), 5.34 (0.5H, br s), 5.16 (0.5H, br s), 4.48-3.93(7H, m), 3.76 (3H, s). 116

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.87 (1H, m),7.79-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H,m), 7.40 (1H, s), 7.36 (1H, br s), 7.27 (1H, br s), 4.55- 4.45 (1H, m),4.45-4.39 (1H, m), 4.31-4.21 (2H, m), 4.01- 3.92 (1H, m), 3.83 (2H, s).117

¹H-NMR (DMSO-D₆) δ: 7.96-7.93 (2H, m), 7.89-7.87 (1H, m), 7.84 (1H, brs), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43(1H, m), 7.40 (1H, br s), 4.58-4.46 (1H, m), 4.45-4.38 (1H, m),4.34-4.17 (2H, m), 4.01-3.91 (1H, m), 3.87 (2H, s), 2.62 (3H, d, J = 4.6Hz). 118

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (2H, m), 7.88-7.87 (1H, m), 7.79-7.76 (1H,m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.40 (1H,br s), 4.54-4.39 (2H, m), 4.32-4.17 (2H, m), 4.20 (2H, s), 3.99-3.87(1H, m), 2.89 (3H, s), 2.81 (3H, s). 119

¹H-NMR (DMSO-D₆) δ: 8.15-8.11 (1H, m), 8.08-8.05 (1H, m), 8.03-7.96 (2H,m), 7.72-7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.44 (1H,s), 4.23-4.14 (1H, m), 2.33- 2.23 (4H, m), 2.13-2.00 (1H, m), 1.87-1.75(1H, m).

TABLE 1-18 compound No. structural formula NMR 120

¹H-NMR (CDCl₃) δ: 7.83-7.63 (5H, m), 7.53-7.48 (1H, m), 7.44-7.39 (1H,m), 4.58-4.06 (5H, m), 3.82-3.72 (3H, m), 3.52-3.40 (1H, m). 121

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.86 (1H, m),7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H,m), 7.41 (1H, br s), 4.58-3.99 (4H, m), 3.55-3.43 (1H, m). 122

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, d, J = 1.5 Hz), 7.98 (1H, br s), 7.86-7.83(1H, m), 7.73- 7.68 (1H, m), 7.53-7.46 (3H, m), 4.43-4.34 (2H, m), 4.13-4.06 (2H, m), 2.75 (3H, s), 2.34-2.26 (2H, m). 123

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.9 Hz), 7.89-7.86 (1H, m),7.80-7.75 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.52 (1H, s),7.48- 7.43 (1H, m), 7.42-7.40 (1H, m), 7.09 (1H, br s), 4.48-4.40 (1H,m), 4.37-4.30 (1H, m), 4.22-4.14 (1H, m), 4.08-4.00 (1H, m), 3.42-3.35(1H, m). 124

¹H-NMR (DMSO-D₆) δ: 8.02-7.97 (1H, m), 7.94 (2H, d, J = 7.7 Hz),7.88-7.86 (1H, m), 7.80-7.75 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H,m), 7.47-7.43 (1H, m), 7.42-7.39 (1H, m), 4.49-4.40 (1H, m), 4.37-4.29(1H, m), 4.22-4.14 (1H, m), 4.08-4.01 (1H, m), 3.41-3.34 (1H, m), 2.62(3H, d, J = 4.6 Hz). 125

¹H-NMR (CDCl₃) δ: 7.89 (0.5H, br s), 7.81 (0.5H, br s), 7.78-7.63 (4H,m), 7.51-7.46 (1H, m), 7.43-7.37 (1H, m), 4.71-4.62 (1H, m), 4.49 (0.5H,br s), 4.38-3.98 (3.5H, m), 3.63-3.48 (1H, m), 2.97 (3H, s), 2.92-2.85(3H, m). 126

¹H-NMR (CDCl₃) δ: 7.72 (1H, d, J = 7.4 Hz), 7.68 (1H, d, J = 7.7 Hz),7.54-7.36 (6H, m), 7.32 (1H, dd, J = 7.7, 0.7 Hz), 7.29-7.24 (1H, m),7.17-7.12 (1H, m), 6.82 (1H, d, J = 7.9 Hz), 2.04 (1H, br s).

TABLE 1-19 compound No. structural formula NMR 127

¹H-NMR (DMSO-D₆) δ: 7.96-7.91 (2H, m), 7.68-7.63 (2H, m), 7.59-7.52 (2H,m), 7.46-7.41 (1H, m), 7.39 (1H, br s), 3.82- 3.35 (8H, m). 128

¹H-NMR (DMSO-D₆) δ: 7.73 (2H, d, J = 8.1 Hz), 7.60-7.57 (1H, m),7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.22 (1H, s), 7.08-7.05 (1H, m),6.96 (1H, dd, J = 8.3, 2.3 Hz), 4.79-4.71 (1H, m), 2.48-2.41 (2H, m),2.13-2.01 (2H, m), 1.85-1.75 (1H, m), 1.74-1.64 (1H, m). 129

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.94-7.90 (2H, m), 7.87(1H, dd, J = 8.0, 1.7 Hz), 7.69-7.65 (1H, m), 7.59-7.51 (4H, m), 7.44-7.40 (1H, m), 7.36 (1H, s), 7.28-7.21 (1H, m). 130

¹H-NMR (DMSO-D₆) δ: 9.46 (1H, br s), 7.76-7.72 (1H, m), 7.67-7.63 (1H,m), 7.54-7.48 (2H, m), 7.41-7.35 (3H, m), 7.26 (1H, s), 3.32 (1.5H, s),3.29 (1.5H, s). 131

¹H-NMR (DMSO-D₆) δ: 8.39 (1H, d, J = 0.9 Hz), 8.10-8.07 (1H, m), 7.88(1H, dd, J = 7.8, 1.2 Hz), 7.86-7.82 (1H, m), 7.73-7.69 (1H, m), 7.59-7.54 (2H, m), 7.49-7.42 (2H, m), 7.36 (1H, s). 132

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.94-7.86 (3H, m),7.78-7.76 (1H, m), 7.71-7.65 (2H, m), 7.57-7.52 (2H, m), 7.49-7.46 (1H,m), 7.44-7.40 (1H, m), 7.36 (1H, s). 133

¹H-NMR (CDCl₃) δ: 7.92-7.58 (5H, m), 7.52-7.47 (1H, m), 7.43-7.38 (1H,m), 5.81 (0.5H, br s), 5.54 (0.5H, br s), 4.22-4.09 (1H, m), 4.06- 3.93(2H, m), 3.82-3.77 (0.5H, m), 3.68-3.62 (0.5H, m), 3.05-2.89 (1H, m),2.05 (3H, s), 1.97 (3H, s).

TABLE 1-20 compound No. structural formula NMR 134

¹H-NMR (CDCl₃) δ: 8.79-8.75 (1H, m), 7.83-7.77 (1H, m), 7.73-7.66 (2H,m), 7.51-7.47 (1H, m), 7.41-7.37 (1H, m), 7.31-7.20 (3H, m), 7.14-7.07(1H, m), 6.66 (1H, d, J = 7.9 Hz). 135 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.92-7.89 (1H, m), 7.72-7.69 (2H, m), 7.59-7.54 (2H,m), 7.48-7.43 (1H, m), 7.31 (1H, s), 4.38- 4.29 (2H, m), 4.12-4.03 (2H,m), 2.68 (3H, s), 2.32-2.24 (2H, m). 136 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.92-7.89 (1H, m), 7.73-7.68 (2H, m), 7.59-7.54 (2H,m), 7.48-7.43 1H, m), 7.31 (1H, s), 4.39- 4.28 (2H, m), 4.11-4.02 (2H,m), 2.68 (3H, s), 2.32-2.23 (2H, m). 137

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (1H, m), 7.92-7.85 (2H, m), 7.83-7.79 (1H,m), 7.69-7.64 (1H, m), 7.56-7.47 (3H, m), 7.43-7.37 (2H, m), 7.33 (1H,s), 7.24-7.20 (1H, m), 2.41 (3H, s). 138

¹H-NMR (CDCl₃) δ: 7.88-7.84 (1H, m), 7.73-7.68 (1H, m), 7.64-7.59 (1H,m), 7.44-7.38 (1H, m), 7.35-7.28 (2H, m), 7.22-7.19 (1H, m), 5.36-5.33(1H, m), 5.09-5.07 (1H, m), 2.66 (1H, br s), 2.16 (3H, s). 139

¹H-NMR (DMSO-D₆) δ: 8.76 (2H, d, J = 5.5 Hz), 7.75 (1H, d, J = 7.5 Hz),7.67 (1H, d, J = 7.5 Hz), 7.54-7.47 (3H, m), 7.37-7.32 (2H, m), 7.32(1H, s), 7.28-7.23 (1H, m), 6.79 (1H, d, J = 7.7 Hz). 140

¹H-NMR (DMSO-D₆) δ: 9.52 (1H, s), 8.05-8.02 (1H, m), 7.94- 7.90 (2H, m),7.75-7.70 (1H, m), 7.64-7.59 (1H, m), 7.52- 7.45 (2H, m), 7.44 (1H, s).

TABLE 1-21 compound No. structural formula NMR 141

¹H-NMR (DMSO-D₆) δ: 8.26-8.23 (1H, m), 8.17 (1H, d, J = 1.4 Hz),8.14-8.11 (1H, m), 7.82- 7.78 (1H, m), 7.74-7.69 (2H, m), 7.65-7.61 (1H,m), 4.45- 4.34 (2H, m), 4.14-4.05 (2H, m), 2.34-2.24 (2H, m). 142

¹H-NMR (DMSO-D₆) δ: 7.98-7.94 (3H, m), 7.75-7.71 (1H, m), 7.65-7.60 (1H,m), 7.53-7.48 (2H, m), 7.46 (1H, s), 2.54 (3H, s). 143

¹H-NMR (CDCl₃) δ: 8.60-8.57 (1H, m), 8.21-8.18 (1H, m), 8.03-8.00 (1H,m), 7.81-7.77 (1H, m), 7.60-7.54 (2H, m), 7.51-7.47 (1H, m), 3.21 (3H,s), 2.96 (1H, br s). 144

¹H-NMR (CDCl₃) δ: 7.95-7.92 (1H, m), 7.74-7.70 (2H, m), 7.68-7.64 (2H,m), 7.51-7.47 (1H, m), 7.40-7.31 (3H, m), 7.11 (1H, dd, J = 5.1, 3.7Hz), 2.79 (1H, br s). 145

¹H-NMR (CDCl₃) δ: 7.91-7.89 (1H, m), 7.70-7.66 (2H, m), 7.65-7.61 (2H,m), 7.52-7.49 (1H, m), 7.48-7.43 (1H, m), 7.43-7.38 (2H, m), 7.36-7.31(1H, m), 2.91 (1H, br s). 146

¹H-NMR (DMSO-D₆) δ: 8.74 (1H, dd, J = 4.9, 1.5 Hz), 8.65 (1H, br s),7.94-7.86 (1H, m), 7.74 (1H, d, J = 7.5 Hz), 7.67 (1H, d, J = 7.3 Hz),7.60 (1H, dd, J = 7.9, 5.1 Hz), 7.52-7.48 (1H, m), 7.39- 7.32 (2H, m),7.31 (1H, s), 7.26-7.22 (1H, m), 6.66 (1H, d, J = 7.7 Hz). 147

¹H-NMR (DMSO-D₆) δ: 8.13-8.11 (1H, m), 7.84 (1H, d, J = 8.3 Hz),7.82-7.79 (1H, m), 7.65 (1H, dd, J = 8.5, 2.0 Hz), 7.64-7.61 (1H, m),7.51-7.47 (1H, m), 7.37-7.32 (1H, m), 7.27 (1H, s), 3.95-3.83 (2H, m),2.56-2.51 (2H, m), 2.13- 2.05 (2H, m).

TABLE 1-22 compound No. structural formula NMR 148

¹H-NMR (CDCl₃) δ: 7.65-7.62 (1H, m), 7.53-7.50 (1H, m), 7.48 (1H, d, J =8.4 Hz), 7.43-7.38 (1H, m), 7.26-7.20 (2H, m), 6.96 (1H, dd, J = 8.4,2.4 Hz), 3.24-3.20 (4H, m), 2.78 (1H, br s), 1.76- 1.68 (4H, m),1.63-1.57 (2H, m). 149

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.93-7.90 (1H, m),7.80-7.78 (1H, m), 7.73-7.65 (2H, m), 7.62-7.52 (2H, m), 7.50-7.33 (5H,m). 150

¹H-NMR (CDCl₃) δ: 7.98-7.90 (2H, m), 7.70-7.65 (2H, m), 7.64-7.52 (3H,m), 7.84-7.40 (4H, m), 7.34 (1H, s). 151

¹H-NMR (CDCl₃) δ: 7.74-7.67 (4H, m), 7.52-7.43 (2H, m), 7.39-7.35 (1H,m), 7.32-7.27 (4H, m), 2.76 (1H, br s), 2.31 (3H, s). 152 (opticallyactive form)

¹H-NMR (CDCl₃) δ: 7.82-7.76 (2H, m), 7.75-7.64 (1H, m), 7.53-7.48 (1H,m), 7.44-7.38 (2H, m), 4.48-3.99 (6H, m), 3.80-3.71 (2H, m), 3.53 (2H,br s), 2.66-2.50 (3H, m), 2.31 (0.5H, br s), 2.03 (0.5H, br s). 153(optically active form)

¹H-NMR (CDCl₃) δ: 7.83-7.73 (3H, m), 7.53-7.38 (3H, m), 4.73-4.65 (1H,m), 4.43-4.32 (2H, m), 4.24-4.11 (1H, m), 3.93-3.86 (1H, m), 3.64-3.56(1H, m), 2.98 (3H, s), 2.91 (3H, s), 2.64 (3H, s). 154

¹H-NMR (CDCl₃) δ: 8.31-8.30 (1H, m), 8.06-8.03 (1H, m), 7.96-7.94 (1H,m), 7.85-7.81 (1H, m), 7.75-7.69 (4H, m), 7.57-7.48 (2H, m), 7.41-7.36(1H, m), 3.96 (3H, s), 2.94 (1H, br s).

TABLE 1-23 compound No. structural formula NMR 155

¹H-NMR (CDCl₃) δ: 8.40-8.38 (1H, m), 8.14-8.11 (1H, m), 7.98-7.95 (1H,m), 7.91-7.88 (1H, m), 7.77-7.69 (4H, m), 7.62-7.57 (1H, m), 7.54-7.49(1H, m), 7.42-7.36 (1H, m), 2.04 (1H, br s). 156

¹H-NMR (DMSO-D₆) δ: 8.22-8.20 (1H, m), 8.18 (1H, br s), 8.00-7.97 (2H,m), 7.94-7.85 (4H, m), 7.70-7.66 (1H, m), 7.61-7.52 (2H, m), 7.47 (1H,br s), 7.44-7.39 (1H, m), 7.38 (1H, s). 157

¹H-NMR (DMSO-D₆) δ: 8.65-8.60 (1H, m), 8.17-8.14 (1H, m), 8.01-7.96 (2H,m), 7.94-7.84 (4H, m), 7.70-7.66 (1H, m), 7.61-7.57 (1H, m), 7.56-7.52(1H, m), 7.44-7.40 (1H, m), 7.39 (1H, s), 2.83 (3H, d, J = 4.4 Hz). 158

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 7.9 Hz), 7.93-7.90 (2H, m), 7.87(1H, dd, J = 7.9, 1.9 Hz), 7.81-7.77 (1H, m), 7.71-7.69 (1H, m), 7.69-7.65 (1H, m), 7.59-7.51 (2H, m), 7.44-7.39 (2H, m), 7.36 (1H, br s),3.05-2.94 (6H, m). 159

¹H-NMR (DMSO-D₆) δ: 8.29 (1H, d, J = 7.7 Hz), 7.89 (2H, s), 7.78-7.72(3H, m), 7.63-7.59 (1H, m), 7.55-7.42 (5H, m). 160

¹H-NMR (CDCl₃) δ: 7.63-7.59 (1H, m), 7.49-7.45 (2H, m), 7.40-7.36 (1H,m), 7.20-7.15 (1H, m), 6.89-6.87 (1H, m), 6.60 (1H, dd, J = 8.4, 2.2Hz), 3.38-3.33 (4H, m), 2.67 (1H, s), 2.07-1.99 (4H, m). 161

¹H-NMR (DMSO-D₆) δ: 7.70-7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H,m), 7.27-7.23 (1H, m), 7.19-7.18 (1H, m), 7.12 (1H, s), 7.06 (1H, dd, J= 8.4, 2.4 Hz), 3.78-3.74 (4H, m), 3.20-3.16 (4H, m).

TABLE 1-24 compound No. structural formula NMR 162

¹H-NMR (DMSO-D₆) δ: 7.69-7.63 (2H, m), 7.57-7.54 (1H, m), 7.44-7.40 (1H,m), 7.27-7.22 (1H, m), 7.19-7.16 (1H, m), 7.10 (1H, s), 7.05 (1H, dd, J= 8.5, 2.3 Hz), 3.23-3.18 (4H, m), 2.49-2.45 (4H, m), 2.23 (3H, s). 163

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.56-7.51 (2H, m), 7.45-7.40 (1H,m), 7.28-7.24 (2H, m), 6.97 (1H, dd, J = 8.3, 2.3 Hz), 3.62-3.57 (4H,m), 3.23-3.18 (4H, m), 2.77 (1H, br s), 1.49 (9H, s). 164

¹H-NMR (DMSO-D₆) δ: 9.11 (2H, br s), 7.72 (2H, d, J = 8.2 Hz), 7.60-7.56(1H, m), 7.47- 7.42 (1H, m), 7.30-7.26 (1H, m), 7.25-7.22 (1H, m), 7.11(1H, dd, J = 8.5, 2.3 Hz), 4.96 (2H, br s), 3.46-3.41 (4H, m), 3.28-3.21(4H, m). 165

¹H-NMR (DMSO-D₆) δ: 7.71-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40 (1H,m), 7.28-7.23 (1H, m), 7.22-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J= 8.3, 2.1 Hz), 3.63-3.58 (4H, m), 3.30-3.11 (4H, m), 2.05 (3H, s). 166

¹H-NMR (DMSO-D₆) δ: 8.49 (1H, s), 7.69-7.65 (2H, m), 7.58- 7.55 (1H, m),7.46-7.41 (1H, m), 7.37-7.35 (1H, m), 7.31- 7.23 (3H, m), 7.18-7.11 (4H,m), 6.91-6.87 (1H, m). 167

¹H-NMR (CDCl₃) δ: 7.86-7.32 (7H, m), 4.63-4.49 (1H, m), 3.76 (3H, s),3.73-3.47 (2H, m), 2.38-2.16 (1H, m), 2.09- 1.82 (3H, m). 168

¹H-NMR (DMSO-D₆) δ: 12.57 (1H, br s), 7.97-7.87 (2H, m), 7.77-7.73 (1H,m), 7.72- 7.61 (2H, m), 7.58-7.50 (1H, m), 7.48-7.38 (2H, m), 4.47- 4.37(1H, m), 3.65-3.46 (2H, m), 2.35-2.22 (1H, m), 2.04- 1.77 (3H, m).

TABLE 1-25 compound No. structural formula NMR 169

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.63-7.60 (1H, m), 7.57 (1H, d, J =7.9 Hz), 7.55-7.54 (1H, m), 7.47-7.43 (1H, m), 7.34-7.29 (2H, m), 2.65(1H, br s), 2.62-2.54 (1H, m), 1.95-1.83 (4H, m), 1.80-1.74 (1H, m),1.49-1.38 (4H, m), 1.34-1.23 (1H, m). 170

¹H-NMR (DMSO-D₆) δ: 7.90-7.86 (2H, m), 7.75-7.74 (1H, m), 7.67-7.61 (2H,m), 7.54-7.50 (1H, m), 7.42-7.33 (3H, m), 7.28 (1H, br s), 7.15 (1H, d,J = 8.1 Hz), 7.09-7.05 (1H, m), 3.80 (3H, s). 171

¹H-NMR (CDCl₃) δ: 7.88-7.87 (1H, m), 7.74-7.64 (4H, m), 7.63-7.57 (2H,m), 7.52-7.48 (1H, m), 7.40-7.36 (1H, m), 7.19-7.13 (2H, m), 2.75 (1H,br s). 172

¹H-NMR (CDCl₃) δ: 7.89-7.87 (1H, m), 7.73-7.64 (4H, m), 7.60-7.56 (2H,m), 7.51-7.46 (1H, m), 7.38-7.33 (1H, m), 7.02-6.98 (2H, m), 3.87 (3H,s), 2.75 (1H, br s). 173

¹H-NMR (CDCl₃) δ: 7.88 (1H, d, J = 7.7 Hz), 7.73-7.67 (3H, m), 7.65-7.63(1H, m), 7.58-7.53 (1H, m), 7.52-7.35 (5H, m), 4.15-4.05 (2H, m), 2.92(1H, s), 1.04-0.99 (3H, m). 174

¹H-NMR (DMSO-D₆) δ: 8.22 (1H, br s), 7.97 (1H, d, J = 7.7 Hz), 7.90 (1H,br s), 7.80 (1H, br s), 7.71-7.67 (2H, m), 7.54-7.49 (1H, m), 7.48- 7.43(1H, m), 7.45 (1H, s), 4.40-4.32 (2H, m), 4.13-4.04 (2H, m), 2.34-2.25(2H, m). 175

¹H-NMR (CDCl₃) δ: 8.15-8.11 (2H, m), 7.96-7.95 (1H, m), 7.75-7.74 (2H,m), 7.73-7.69 (4H, m), 7.53-7.49 (1H, m), 7.42-7.37 (1H, m), 4.41 (2H,q, J = 7.1 Hz), 2.85 (1H, s), 1.42 (3H, t, J = 7.2 Hz).

TABLE 1-26 compound No. structural formula NMR 176

¹H-NMR (DMSO-D₆) δ: 7.95-7.23 (9H, m), 7.01-6.92 (1H, m), 4.41-4.36(0.8H, m), 4.25- 4.17 (0.2H, m), 3.66-3.56 (1.2H, m), 3.49-3.38 (0.8H,m), 2.26-2.11 (1H, m), 1.95- 1.75 (3H, m). 177

¹H-NMR (DMSO-D₆) δ: 7.95-7.30 (8H, m), 4.45-4.39 (0.7H, m), 4.21-4.13(0.3H, m), 3.68- 3.55 (1.4H, m), 3.49-3.38 (0.6H, m), 2.63-2.62 (2.1H,m), 2.52-2.49 (0.4H, m), 2.40-2.39 (0.5H, m), 2.23- 2.11 (1H, m),1.97-1.74 (3H, m). 178

¹H-NMR (DMSO-D₆) δ: 7.95-7.86 (2H, m), 7.75-7.71 (0.7H, m), 7.69-7.64(2H, m), 7.57-7.38 (3H, m), 7.31 (0.3H, d, J = 7.4 Hz), 4.98-4.93 (0.7H,m), 4.78-4.69 (0.3H, m), 3.70- 3.45 (2H, m), 3.11 (2.1H, s), 2.86 (2.1H,s), 2.67 (0.4H, s), 2.64 (0.4H, s), 2.62 (0.5H, s), 2.58 (0.5H, s),2.34-2.23 (1H, m), 1.97-1.71 (3H, m). 179

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.9 Hz), 7.92-7.89 (1H, m), 7.88(1H, br s), 7.83 (1H, dd, J = 7.9, 1.8 Hz), 7.76-7.73 (2H, m), 7.69-7.65 (1H, m), 7.58-7.51 (3H, m), 7.44-7.39 (1H, m), 7.35 (1H, br s). 180

¹H-NMR (DMSO-D₆) δ: 12.88 (1H, br s), 7.89 (2H, d, J = 7.9 Hz),7.79-7.75 (1H, m), 7.67-7.64 (1H, m), 7.63-7.58 (2H, m), 7.55-7.46 (3H,m), 7.44-7.38 (2H, m), 7.31 (1H, br s). 181

¹H-NMR (CDCl₃) δ: 7.91-7.90 (1H, m), 7.73-7.66 (4H, m), 7.54 (2H, d, J =8.1 Hz), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 7.28 (2H, d, J = 8.6 Hz),2.76 (1H, s), 2.41 (3H, s). 182

¹H-NMR (DMSO-D₆) δ: 7.88 (2H, d, J = 7.7 Hz), 7.76 (1H, br s), 7.70 (1H,br s), 7.67- 7.64 (1H, m), 7.57 (1H, dd, J = 7.9, 1.6 Hz), 7.55-7.37(6H, m), 7.34 (1H, br s), 7.29 (1H, s).

TABLE 1-27 compound No. structural formula NMR 183

¹H-NMR (DMSO-D₆) δ: 8.19-8.14 (1H, m), 7.91-7.86 (2H, m), 7.67-7.63 (2H,m), 7.56-7.50 (3H, m), 7.47-7.42 (3H, m), 7.42-7.37 (1H, m), 7.26 (1H,s), 2.59 (3H, d, J = 4.6 Hz). 184

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, d, J = 7.7 Hz), 7.90 (1H, d, J = 7.5 Hz),7.68-7.64 (1H, m), 7.63 (1H, br s), 7.57-7.45 (5H, m), 7.43-7.39 (1H,m), 7.38-7.36 (1H, m), 7.26 (1H, s), 2.77 (3H, br s), 2.52- 2.43 (3H,m). 185

¹H-NMR (DMSO-D₆) δ: 8.71-8.68 (2H, m), 8.34-8.31 (1H, m), 8.06 (1H, d, J= 1.5 Hz), 8.01-8.00 (1H, m), 7.83-7.80 (2H, m), 7.78-7.74 (1H, m),7.66-7.61 (1H, m), 7.58 (1H, s), 7.57-7.52 (1H, m). 186

¹H-NMR (DMSO-D₆) δ: 7.72-7.68 (2H, m), 7.58-7.55 (1H, m), 7.46-7.42 (1H,m), 7.38-7.33 (2H, m), 7.29-7.25 (1H, m), 7.19-7.17 (1H, m), 7.16 (1H,s), 7.15-7.11 (2H, m), 7.08- 7.03 (2H, m), 3.32 (3H, s). 187

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.62-7.58 (2H, m), 7.49-7.44 (1H,m), 7.40-7.35 (3H, m), 7.34-7.30 (1H, m), 7.18-7.13 (1H, m), 7.09 (1H,dd, J = 8.3, 2.3 Hz), 7.07- 7.04 (2H, m), 2.69 (1H, s). 188

¹H-NMR (DMSO-D₆) δ: 8.08-8.05 (2H, m), 8.01-7.99 (1H, m), 7.96-7.89 (3H,m), 7.87-7.83 (2H, m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.45-7.40(1H, m), 7.39 (1H, br s). 189

¹H-NMR (CDCl₃) δ: 7.74-7.68 (4H, m), 7.58-7.54 (1H, m), 7.52-7.47 (2H,m), 7.45-7.33 (4H, m), 4.64 (1H, d, J = 13.2 Hz), 4.60 (1H, d, J = 12.8Hz), 1.78 (1H, br s).

TABLE 1-28 compound No. structural formula NMR 190

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, br s), 7.92 (1H, d, J = 7.7 Hz), 7.89 (1H,d, J = 7.3 Hz), 7.67-7.64 (2H, m), 7.55- 7.50 (2H, m), 7.43-7.30 (5H,m), 7.27 (1H, s), 1.88 (3H, br s). 191

¹H-NMR (DMSO-D₆) δ: 8.54-8.49 (1H, m), 8.00-7.88 (6H, m), 7.83-7.79 (2H,m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.45-7.40 (1H, m), 7.37 (1H,s), 2.82 (3H, d, J = 4.6 Hz). 192

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.93-7.90 (2H, m), 7.87(1H, dd, J = 7.9, 1.6 Hz), 7.79-7.76 (2H, m), 7.69-7.66 (1H, m), 7.56-7.52 (3H, m), 7.44-7.40 (1H, m), 7.37 (1H, s), 3.06-2.92 (6H, m). 193

¹H-NMR (DMSO-D₆) δ: 7.85-7.82 (2H, m), 7.77-7.75 (1H, m), 7.68 (1H, dd,J = 7.9, 1.6 Hz), 7.65-7.61 (1H, m), 7.52- 7.47 (1H, m), 7.43-7.39 (2H,m), 7.38-7.33 (1H, m), 7.25 (1H, s), 6.69-6.65 (2H, m), 5.31 (2H, s).194

¹H-NMR (CDCl₃) δ: 7.93-7.91 (1H, m), 7.75-7.63 (6H, m), 7.52-7.45 (3H,m), 7.40-7.35 (1H, m), 4.77 (2H, d, J = 5.5 Hz), 2.82 (1H, s), 1.69 (1H,t, J = 6.0 Hz). 195

¹H-NMR (DMSO-D₆) δ: 7.94-7.90 (2H, m), 7.77-7.72 (1H, m), 7.69-7.61 (2H,m), 7.56-7.52 (1H, m), 7.46-7.41 (1H, m), 7.37 (0.5H, s), 7.33 (0.5H,s), 4.83-4.78 (0.5H, m), 4.21- 4.12 (0.5H, m), 3.65-3.00 (5H, m),2.01-1.64 (4H, m). 196

¹H-NMR (DMSO-D₆) δ: 8.50-8.47 (1H, m), 7.88-7.83 (2H, m), 7.73-7.69 (1H,m), 7.60-7.56 (1H, m), 7.52-7.48 (1H, m), 7.42 (1H, s), 2.39 (3H, s).

TABLE 1-29 compound No. structural formula NMR 197

¹H-NMR (DMSO-D₆) δ: 10.07 (1H, br s), 7.92 (1H, d, J = 7.9 Hz), 7.88(1H, d, J = 7.4 Hz), 7.87-7.85 (1H, m), 7.79 (1H, dd, J = 7.9, 1.6 Hz),7.74-7.70 (2H, m), 7.68-7.64 (3H, m), 7.54- 7.50 (1H, m), 7.42-7.37 (1H,m), 7.32 (1H, s), 2.08 (3H, s). 198

¹H-NMR (DMSO-D₆) δ: 8.53 (1H, d, J = 5.1 Hz), 8.03- 7.93 (4H, m),7.70-7.67 (1H, m), 7.64-7.62 (1H, m), 7.58-7.53 (2H, m), 7.46- 7.42 (1H,m), 7.40 (1H, s), 2.56 (3H, s). 199

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, br s), 8.03-7.97 (3H, m), 7.95-7.88 (3H,m), 7.82-7.78 (2H, m), 7.69- 7.66 (1H, m), 7.56-7.52 (1H, m), 7.44-7.40(1H, m), 7.39 (1H, br s), 7.36 (1H, s). 200

¹H-NMR (DMSO-D₆) δ: 7.96- 7.92 (2H, m), 7.89-7.86 (1H, m), 7.80-7.76(1H, m), 7.69-7.65 (1H, m), 7.58- 7.53 (1H, m), 7.47-7.43 (1H, m), 7.41(1H, br s), 4.54-4.38 (2H, m), 4.31- 4.22 (1H, m), 4.13-4.05 (1H, m),3.81-3.73 (1H, m), 3.33-3.27 (2H, m), 3.21- 3.16 (2H, m), 1.10-1.01 (6H,m). 201

¹H-NMR (DMSO-D₆) δ: 7.96- 7.93 (2H, m), 7.88-7.86 (1H, m), 7.80-7.76(1H, m), 7.69-7.65 (1H, m), 7.58- 7.53 (1H, m), 7.47-7.43 (1H, m), 7.41(1H, br s), 4.55-4.38 (2H, m), 4.30- 4.21 (1H, m), 4.17-4.09 (1H, m),3.72-3.64 (1H, m), 3.34-3.27 (4H, m), 1.90- 1.82 (2H, m), 1.81-1.73 (2H,m). 202

¹H-NMR (DMSO-D₆) δ: 7.97- 7.93 (2H, m), 7.89-7.86 (1H, m), 7.80-7.76(1H, m), 7.69-7.66 (1H, m), 7.58- 7.53 (1H, m), 7.47-7.43 (1H, m), 7.42(1H, br s), 4.55-4.41 (2H, m), 4.31- 4.23 (1H, m), 4.17-4.07 (1H, m),3.81-3.72 (1H, m), 3.48-3.43 (2H, m), 3.25- 3.20 (2H, m), 1.61-1.54 (2H,m), 1.50-1.41 (4H, m).

TABLE 1-30 compound No. structural formula NMR 203

¹H-NMR (DMSO-D₆) δ: 7.96- 7.93 (2H, m), 7.88-7.86 (1H, m), 7.80-7.76(1H, m), 7.69-7.65 (1H, m), 7.58- 7.53 (1H, m), 7.48-7.43 (1H, m), 7.42(1H, br s), 4.74 (1H, d, J = 3.9 Hz), 4.55-4.39 (2H, m), 4.32- 4.23 (1H,m), 4.16-4.07 (1H, m), 3.94-3.86 (1H, m), 3.82-3.74 (1H, m), 3.73- 3.65(1H, m), 3.49-3.41 (1H, m), 3.12-3.01 (2H, m), 1.76-1.66 (2H, m), 1.36-1.22 (2H, m). 204

¹H-NMR (DMSO-D₆) δ: 8.61 (1H, d, J = 4.6 Hz), 8.39 (1H, d, J = 5.1 Hz),7.75 (1H, d, J = 6.8 Hz), 7.67 (1H, d, J = 7.3 Hz), 7.56- 7.44 (2H, m),7.38-7.28 (3H, m), 7.26-7.19 (1H, m), 6.38-6.29 (1H, m), 2.07- 1.99 (3H,m). 205

¹H-NMR (CDCl₃) δ: 7.88-7.85 (1H, m), 7.73-7.63 (4H, m), 7.55-7.51 (2H,m), 7.51- 7.46 (1H, m), 7.38-7.34 (1H, m), 6.95-6.91 (2H, m), 4.82 (1H,s), 2.74 (1H, s). 206

¹H-NMR (DMSO-D₆) δ: 7.95- 7.91 (2H, m), 7.75-7.73 (1H, m), 7.70-7.65(2H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.41-7.37 (1H, m),3.79-3.47 (7H, m), 3.30-3.18 (1H, m), 2.26- 2.00 (2H, m). 207

¹H-NMR (DMSO-D₆) δ: 7.70- 7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40(1H, m), 7.28-7.23 (1H, m), 7.21- 7.19 (1H, m), 7.15 (1H, s), 7.07 (1H,dd, J = 8.6, 2.3 Hz), 3.67-3.56 (4H, m), 3.27-3.13 (4H, m), 2.37 (2H, q,J = 7.4 Hz), 1.02 (3H, t, J = 7.4 Hz). 208

¹H-NMR (DMSO-D₆) δ: 7.71- 7.67 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40(1H, m), 7.28-7.23 (1H, m), 7.22- 7.20 (1H, m), 7.15 (1H, s), 7.08 (1H,dd, J = 8.5, 2.2 Hz), 3.74-3.58 (4H, m), 3.27-3.13 (4H, m), 2.96- 2.88(1H, m), 1.04 (3H, s), 1.02 (3H, s). 209

¹H-NMR (DMSO-D₆) δ: 7.71- 7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.41(1H, m), 7.28-7.23 (1H, m), 7.21- 7.19 (1H, m), 7.14 (1H, s), 7.07 (1H,dd, J = 8.3, 2.3 Hz), 3.75-3.69 (4H, m), 3.23-3.16 (4H, m), 1.23 (9H,s).

TABLE 1-31 compound No. structural formula NMR 210

¹H-NMR (DMSO-D₆) δ: 7.71- 7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40(1H, m), 7.28-7.23 (1H, m), 7.21- 7.19 (1H, m), 7.15 (1H, s), 7.07 (1H,dd, J = 8.5, 2.2 Hz), 3.64 (3H, s), 3.56- 3.51 (4H, m), 3.23-3.18 (4H,m). 211

¹H-NMR (DMSO-D₆) δ: 7.70- 7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40(1H, m), 7.28-7.23 (1H, m), 7.21- 7.19 (1H, m), 7.15 (1H, s), 7.07 (1H,dd, J = 8.3, 2.3 Hz), 4.08 (2H, q, J = 7.1 Hz), 3.57-3.50 (4H, m),3.24-3.17 (4H, m), 1.21 (3H, t, J = 7.1 Hz). 212

¹H-NMR (DMSO-D₆) δ: 7.71- 7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40(1H, m), 7.28-7.23 (1H, m), 7.21- 7.19 (1H, m), 7.15 (1H, s), 7.06 (1H,dd, J = 8.3, 2.1 Hz), 4.86-4.74 (1H, m), 3.55-3.49 (4H, m), 3.24- 3.15(4H, m), 1.21 (6H, d, J = 6.3 Hz). 213

¹H-NMR (DMSO-D₆) δ: 8.88 (1H, d, J = 2.0 Hz), 8.17- 8.16 (1H, m),7.97-7.94 (1H, m), 7.78-7.75 (1H, m), 7.68-7.58 (2H, m), 7.64 (1H, s),4.45-4.35 (2H, m), 4.15-4.06 (2H, m), 2.34- 2.26 (2H, m). 214

¹H-NMR (CDCl₃) δ: 7.92-7.85 (3H, m), 7.78-7.65 (5H, m), 7.61-7.56 (1H,m), 7.54- 7.49 (1H, m), 7.43-7.38 (1H, m), 2.87 (1H, br s). 215

¹H-NMR (DMSO-D₆) δ: 7.94- 7.91 (2H, m), 7.77-7.73 (1H, m), 7.70-7.65(2H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.40-7.35 (1H, m), 5.03(0.5H, d, J = 3.7 Hz), 4.97 (0.5H, d, J = 3.3 Hz), 4.37-4.32 (0.5H, m),4.29-4.24 (0.5H, m), 3.69-3.50 (2H, m), 3.49- 3.20 (2H, m), 2.03-1.76(2H, m). 216

¹H-NMR (DMSO-D₆) δ: 7.94- 7.90 (2H, m), 7.76-7.72 (1H, m), 7.71-7.64(2H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.40-7.34 (1H, m),3.77-3.60 (1H, m), 3.57-3.43 (2H, m), 3.30- 3.20 (1H, m), 2.78-2.63 (1H,m), 2.19 (3H, s), 2.10-2.09 (3H, m), 2.07- 1.98 (1H, m), 1.81-1.68 (1H,m).

TABLE 1-32 compound No. structural formula NMR 217

¹H-NMR (DMSO-D₆) δ: 12.52 (1H, br s), 7.95-7.91 (2H, m), 7.76-7.73 (1H,m), 7.71-7.64 (2H, m), 7.57- 7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.35(1H, m), 3.77-3.47 (4H, m), 3.20- 3.05 (1H, m), 2.24-1.96 (2H, m). 218

¹H-NMR (DMSO-D₆) δ: 7.69- 7.62 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39(1H, m), 7.27-7.22 (1H, m), 7.20- 7.16 (1H, m), 7.11 (1H, s), 7.06 (1H,dd, J = 8.6, 2.4 Hz), 3.74-3.66 (2H, m), 3.63 (3H, s), 2.90-2.82 (2H,m), 2.61-2.52 (1H, m), 2.00-1.90 (2H, m), 1.74- 1.62 (2H, m). 219

¹H-NMR (CDCl₃) δ: 8.37 (1H, dd, J = 8.8, 5.1 Hz), 7.93 (1H, dd, J = 7.8,1.2 Hz), 7.87-7.84 (1H, m), 7.44- 7.37 (2H, m), 7.19-7.13 (1H, m), 4.01(3H, s), 2.77 (1H, s). 220

¹H-NMR (CDCl₃) δ: 8.12 (1H, dd, J = 10.4, 2.4 Hz), 7.95 (1H, dd, J =7.9, 1.1 Hz), 7.89-7.86 (1H, m), 7.70- 7.65 (1H, m), 7.47-7.41 (1H, m),7.12-7.07 (1H, m), 4.02 (3H, s), 2.72 (1H, s). 221

¹H-NMR (CDCl₃) δ: 8.36-8.32 (1H, m), 7.94 (1H, dd, J = 8.7, 5.2 Hz),7.75-7.72 (1H, m), 7.53-7.48 (1H, m), 7.47-7.42 (1H, m), 7.09- 7.04 (1H,m), 4.01 (3H, s), 3.21-3.19 (1H, m). 222

¹H-NMR (DMSO-D₆) δ: 7.78- 7.71 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(2H, m), 7.34-7.25 (2H, m), 3.72- 3.63 (2H, m), 3.08 (2H, br s),2.57-2.46 (1H, m), 2.04- 1.96 (2H, m), 1.89-1.72 (2H, m). 223

¹H-NMR (DMSO-D₆) δ: 7.68- 7.63 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39(1H, m), 7.26-7.22 (1H, m), 7.19- 7.17 (1H, m), 7.11 (1H, s), 7.06 (1H,dd, J = 8.5, 2.3 Hz), 4.09 (2H, q, J = 7.1 Hz), 3.74-3.66 (2H, m),2.90-2.82 (2H, m), 2.58- 2.48 (1H, m), 1.98-1.90 (2H, m), 1.73-1.62 (2H,m), 1.20 (3H, t, J = 7.1 Hz).

TABLE 1-33 compound No. structural formula NMR 224

¹H-NMR (CDCl₃) δ: 7.93-7.91 (1H, m), 7.79-7.70 (8H, m), 7.54-7.50 (1H,m), 7.43- 7.39 (1H, m), 2.81 (1H, br s). 225

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.7 Hz), 7.75- 7.72 (1H, m),7.69-7.65 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40- 7.35 (1H,m), 4.75-4.63 (1H, m), 3.64-3.21 (6H, m), 2.42-2.24 (1H, m), 2.00- 1.85(1H, m), 1.72-1.59 (1H, m). 226

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.4 Hz), 7.76- 7.73 (1H, m),7.70-7.64 (2H, m), 7.56-7.36 (4H, m), 7.00-6.91 (1H, m), 3.75- 3.43 (4H,m), 3.04-2.90 (1H, m), 2.17-1.91 (2H, m). 227

¹H-NMR (DMSO-D₆) δ: 8.01- 7.96 (0.5H, m), 7.92 (2H, d, J = 7.7 Hz),7.90-7.85 (0.5H, m), 7.75-7.72 (1H, m), 7.70-7.64 (2H, m), 7.57-7.52(1H, m), 7.46- 7.35 (2H, m), 3.73-3.43 (4H, m), 3.03-2.88 (1H, m), 2.62(1.5H, d, J = 4.4 Hz), 2.55 (1.5H, d, J = 4.4 Hz), 2.16-1.91 (2H, m).228

¹H-NMR (DMSO-D₆) δ: 7.94- 7.90 (2H, m), 7.75-7.72 (1H, m), 7.69-7.64(2H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.38-7.36 (1H, m),3.62-3.37 (3H, m), 3.24-3.08 (2H, m), 2.30 (1.4H, s), 2.18 (1.6H, d, J =4.9 Hz), 2.05-1.87 (1H, m), 1.79-1.68 (1H, m). 229

¹H-NMR (DMSO-D₆) δ: 7.94- 7.91 (2H, m), 7.76-7.72 (1H, m), 7.71-7.64(2H, m), 7.57-7.52 (1H, m), 7.46- 7.36 (2H, m), 3.77-3.40 (5H, m), 3.07(1.5H, s), 2.98 (1.5H, s), 2.86 (1.5H, s), 2.80 (1.5H, s), 2.22- 2.03(1H, m), 2.01-1.89 (1H, m). 230

¹H-NMR (DMSO-D₆) δ: 7.66 (1H, d, J = 7.3 Hz), 7.64 (1H, d, J = 8.6 Hz),7.57- 7.53 (1H, m), 7.44-7.39 (1H, m), 7.29 (1H, s), 7.26-7.21 (1H, m),7.19- 7.16 (1H, m), 7.11 (1H, s), 7.05 (1H, dd, J = 8.5, 2.3 Hz), 6.77(1H, br s), 3.81- 3.73 (2H, m), 2.81-2.73 (2H, m), 2.33-2.24 (1H, m),1.84-1.77 (2H, m), 1.71- 1.60 (2H, m).

TABLE 1-34 compound No. structural formula NMR 231

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (1H, m), 7.68-7.62 (2H, m), 7.57-7.53(1H, m), 7.44-7.39 (1H, m), 7.26- 7.21 (1H, m), 7.19-7.16 (1H, m), 7.11(1H, s), 7.05 (1H, dd, J = 8.6, 2.4 Hz), 3.82-3.73 (2H, m), 2.81- 2.72(2H, m), 2.58 (3H, d, J = 4.6 Hz), 2.34-2.24 (1H, m), 1.81-1.74 (2H, m),1.73-1.61 (2H, m). 232

¹H-NMR (DMSO-D₆) δ: 7.68- 7.62 (2H, m), 7.57-7.53 (1H, m), 7.45-7.39(1H, m), 7.27-7.21 (1H, m), 7.19- 7.16 (1H, m), 7.11 (1H, s), 7.05 (1H,dd, J = 8.4, 2.2 Hz), 3.83-3.74 (2H, m), 3.06 (3H, s), 2.90-2.78 (3H,m), 2.82 (3H, s), 1.77- 1.60 (4H, m). 233

¹H-NMR (DMSO-D₆) δ: 8.33- 8.30 (1H, m), 8.11-8.07 (2H, m), 7.99 (1H, d,J = 1.5 Hz), 7.97-7.92 (3H, m), 7.77-7.74 (1H, m), 7.65- 7.60 (1H, m),7.58 (1H, s), 7.56-7.51 (1H, m), 4.36 (2H, q, J = 7.1 Hz), 1.36 (3H, t,J = 7.2 Hz). 234

¹H-NMR (DMSO-D₆) δ: 13.08 (1H, br s), 8.32-8.29 (1H, m), 8.09-8.05 (2H,m), 7.98 (1H, d, J = 1.5 Hz), 7.96- 7.94 (1H, m), 7.92-7.88 (2H, m),7.77-7.73 (1H, m), 7.65-7.60 (1H, m), 7.59- 7.50 (2H, m). 235

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, s), 7.88-7.85 (1H, m), 7.73-7.70 (1H, m),7.63- 7.59 (1H, m), 7.58-7.53 (1H, m), 7.45 (1H, s), 4.08 (3H, s),4.06-3.95 (4H, m), 2.30-2.20 (2H, m). 236

¹H-NMR (DMSO-D₆) δ: 8.01 (1H, d, J = 7.9 Hz), 7.99- 7.92 (5H, m), 7.83(1H, dd, J = 8.1, 1.6 Hz), 7.70-7.67 (1H, m), 7.58-7.53 (1H, m),7.46-7.42 (1H, m), 7.40 (1H, s), 3.90 (3H, s). 237

¹H-NMR (DMSO-D₆) δ: 7.87- 7.83 (2H, m), 7.65-7.61 (1H, m), 7.53-7.49(1H, m), 7.40-7.33 (2H, m), 7.34 (1H, s), 7.26 (1H, dd, J = 8.2, 2.2Hz), 3.07 (3H, s), 2.93 (3H, s).

TABLE 1-35 compound No. structural formula NMR 238

¹H-NMR (DMSO-D₆) δ: 13.44 (1H, br s), 8.02-7.99 (1H, m), 7.97-7.92 (4H,m), 7.89-7.86 (1H, m), 7.80- 7.77 (1H, m), 7.70-7.66 (1H, m), 7.57-7.52(1H, m), 7.46-7.41 (1H, m), 7.39 (1H, br s). 239

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, d, J = 7.9 Hz), 7.95- 7.88 (4H, m), 7.81(1H, d, J = 1.6 Hz), 7.73 (1H, dd, J = 8.0, 1.5 Hz), 7.69-7.62 (2H, m),7.59-7.57 (1H, m), 7.55-7.52 (1H, m), 7.45- 7.40 (1H, m), 7.38 (1H, s).240

¹H-NMR (DMSO-D₆) δ: 8.43- 8.37 (1H, m), 8.01-7.97 (1H, m), 7.96-7.88(3H, m), 7.83-7.81 (1H, m), 7.75- 7.71 (1H, m), 7.70-7.66 (1H, m),7.58-7.52 (2H, m), 7.45-7.40 (1H, m), 7.37 (1H, s), 2.79 (3H, d, J = 4.4Hz). 241

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, d, J = 7.9 Hz), 7.95- 7.90 (3H, m), 7.86(1H, d, J = 1.6 Hz), 7.76 (1H, dd, J = 8.1, 1.6 Hz), 7.69-7.66 (1H, m),7.57-7.52 (1H, m), 7.48 (1H, d, J = 7.9 Hz), 7.45-7.40 (1H, m), 7.38(1H, s), 3.04 (3H, s), 2.84 (3H, s). 242

¹H-NMR (DMSO-D₆) δ: 8.77 (1H, dd, J = 4.9, 1.8 Hz), 8.68 (1H, br s),7.94 (2H, br s), 7.72-7.68 (1H, m), 7.64-7.59 (1H, m), 7.58 (1H, d, J =1.5 Hz), 7.48 (1H, s), 7.42-7.37 (1H, m), 7.31-7.26 (1H, m), 6.71 (1H,d, J = 7.5 Hz), 4.42- 4.33 (2H, m), 4.13-4.05 (2H, m), 2.34-2.24 (2H,m). 243

¹H-NMR (DMSO-D₆) δ: 8.78- 8.76 (1H, m), 8.70-8.66 (1H, m), 7.98-7.91(1H, m), 7.72 (1H, d, J = 1.1 Hz), 7.68 (1H, d, J = 7.5 Hz), 7.63-7.59(1H, m), 7.54- 7.50 (2H, m), 7.40-7.35 (1H, m), 7.29-7.24 (1H, m), 6.63(1H, d, J = 7.7 Hz). 244

¹H-NMR (DMSO-D₆) δ: 7.79- 7.76 (1H, m), 7.71 (1H, d, J = 7.9 Hz),7.62-7.58 (1H, m), 7.49-7.45 (1H, m), 7.36-7.30 (2H, m), 7.19 (1H, dd, J= 7.9, 1.5 Hz), 7.16 (1H, s), 2.06-1.98 (1H, m), 1.04-0.98 (2H, m),0.75-0.68 (2H, m).

TABLE 1-36 compound No. structural formula NMR 245

¹H-NMR (CDCl₃) δ: 7.98-7.96 (1H, m), 7.93 (1H, s), 7.79-7.76 (1H, m),7.75- 7.67 (3H, m), 7.53-7.49 (1H, m), 7.42-7.37 (2H, m), 2.96 (1H, brs). 246

¹H-NMR (DMSO-D₆) δ: 7.95- 7.90 (2H, m), 7.80-7.64 (3H, m), 7.57-7.52(1H, m), 7.46-7.41 (1H, m), 7.39- 7.34 (1H, m), 5.16-4.47 (1H, m),3.77-3.34 (4H, m), 2.92-2.71 (3H, m), 2.14- 1.91 (5H, m). 247

¹H-NMR (CDCl₃) δ: 8.42 (1H, s), 8.21-8.18 (1H, m), 7.80-7.76 (2H, m),7.75- 7.72 (1H, m), 7.56-7.52 (1H, m), 7.49-7.44 (1H, m), 3.48 (1H, brs), 2.37 (3H, s). 248

¹H-NMR (CDCl₃) δ: 7.70-7.67 (2H, m), 7.63 (1H, d, J = 7.7 Hz), 7.58 (1H,d, J = 7.9 Hz), 7.48-7.44 (1H, m), 7.43-7.40 (1H, m), 7.36- 7.31 (1H,m), 6.49-6.43 (1H, m), 6.38-6.29 (1H, m), 2.70 (1H, s), 1.92 (3H, d, J =6.3 Hz). 249

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.02 (2H, t, J = 6.4 Hz),2.70 (1H, s), 1.84-1.76 (2H, m), 1.57- 1.47 (2H, m), 1.02-0.97 (3H, m).250

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.7 Hz), 7.73 (1H, d, J = 7.7 Hz),7.70 (1H, d, J = 7.2 Hz), 7.60- 7.54 (2H, m), 7.45-7.36 (2H, m), 7.37(1H, s), 4.54 (3H, s). 251

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 7.7 Hz), 7.73- 7.68 (2H, m),7.66-7.61 (1H, m), 7.48 (1H, s), 7.45-7.41 (1H, m), 7.39- 7.34 (1H, m),6.44 (1H, d, J = 7.4 Hz), 3.92 (3H, s).

TABLE 1-37 compound No. structural formula NMR 252

¹H-NMR (CDCl₃) δ: 7.88-7.86 (1H, m), 7.73-7.69 (1H, m), 7.67-7.58 (3H,m), 7.56- 7.53 (2H, m), 7.50-7.46 (1H, m), 7.41-7.33 (3H, m), 7.30-7.26(1H, m), 7.20 (1H, d, J = 16.5 Hz), 7.15 (1H, d, J = 16.3 Hz), 2.75 (1H,br s). 253

¹H-NMR (DMSO-D₆) δ: 7.75- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.47-7.43(1H, m), 7.31-7.27 (1H, m), 7.20 (1H, s), 7.15-7.13 (1H, m), 7.05 (1H,dd, J = 8.4, 2.4 Hz), 3.84 (2H, d, J = 6.2 Hz), 1.86-1.64 (6H, m), 1.32-1.02 (5H, m). 254

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.47-7.43(1H, m), 7.31-7.27 (1H, m), 7.20 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H,dd, J = 8.4, 2.4 Hz), 3.91 (2H, d, J = 7.1 Hz), 2.39-2.27 (1H, m),1.84-1.74 (2H, m), 1.68- 1.50 (4H, m), 1.41-1.31 (2H, m). 255

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H,dd, J = 8.4, 2.4 Hz), 4.01 (2H, d, J = 6.6 Hz), 2.78-2.70 (1H, m),2.14-2.04 (2H, m), 1.97- 1.80 (4H, m). 256

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43(1H, m), 7.31-7.26 (1H, m), 7.21 (1H, s), 7.15-7.13 (1H, m), 7.05 (1H,dd, J = 8.3, 2.3 Hz), 3.88 (2H, d, J = 7.0 Hz), 1.29-1.19 (1H, m),0.61-0.56 (2H, m), 0.38- 0.33 (2H, m). 257

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.25 (1H, m), 7.24-7.22 (1H, m), 6.99-6.95 (1H, m), 4.18-4.12(2H, m), 4.07 (2H, t, J = 6.0 Hz), 2.77 (1H, s), 2.53 (2H, t, J = 7.3Hz), 2.17-2.10 (2H, m), 1.29-1.24 (3H, m). 258

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 7.76-7.73 (2H, m), 7.61-7.56 (1H,m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.21 (1H, m), 7.18-7.14(1H, m), 7.06 (1H, dd, J = 8.2, 2.0 Hz), 4.05 (2H, t, J = 6.4 Hz), 2.41(2H, t, J = 7.3 Hz), 2.01-1.93 (2H, m).

TABLE 1-38 compound No. structural formula NMR 259

¹H-NMR (DMSO-D₆) δ: 7.75- 7.71 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.15-7.12 (1H, m), 7.08-7.05(1H, m), 4.43- 4.37 (1H, m), 2.00-1.91 (2H, m), 1.77-1.68 (2H, m),1.59-1.22 (6H, m). 260

¹H-NMR (DMSO-D₆) δ: 7.75- 7.71 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.15-7.12 (1H, m), 7.08-7.05(1H, m), 4.43- 4.37 (1H, m), 2.00-1.91 (2H, m), 1.77-1.68 (2H, m),1.59-1.22 (6H, m). 261

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.61-7.56 (2H, m), 7.49-7.44(1H, m), 7.33-7.28 (1H, m), 7.26- 7.23 (2H, m), 7.23 (1H, s), 7.17 (1H,dd, J = 8.4, 2.4 Hz), 7.05 (1H, dd, J = 5.1, 3.5 Hz), 5.38 (1H, d, J =12.1 Hz), 5.35 (1H, d, J = 12.1 Hz). 262

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.51-7.23(9H, m), 7.16 (1H, dd, J = 8.3, 2.3 Hz), 5.17 (2H, s). 263

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.48 (1H, s), 7.47 (1H, s),7.36-7.22 (5H, m), 4.00 (3H, s), 3.20 (1H, br s). 264

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.45-7.41 (1H,m), 7.29- 7.25 (1H, m), 7.24-7.23 (1H, m), 6.98 (1H, dd, J = 8.3, 2.3Hz), 3.78 (2H, d, J = 6.6 Hz), 2.66 (1H, s), 2.17-2.05 (1H, m), 1.06(3H, d, J = 0.9 Hz), 1.04 (3H, d, J = 0.9 Hz). 265

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.23 (2H, m), 6.99 (1H, dd, J = 8.2, 2.4 Hz), 3.98 (2H, t, J =6.5 Hz), 2.66 (1H, s), 1.89-1.79 (2H, m), 1.06 (3H, t, J = 7.4 Hz).

TABLE 1-39 compound No. structural formula NMR 266

¹H-NMR (CDCl₃) δ: 7.87-7.85 (1H, m), 7.76-7.64 (4H, m), 7.54-7.49 (3H,m), 7.43- 7.36 (2H, m), 2.77 (1H, s). 267

¹H-NMR (DMSO-D₆) δ: 8.17- 8.13 (1H, m), 7.92-7.89 (1H, m), 7.88 (1H, dd,J = 7.9, 1.1 Hz), 7.74-7.71 (1H, m), 7.63-7.58 (1H, m), 7.53-7.45 (2H,m), 7.42 (1H, s), 2.66 (3H, s). 268

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, d, J = 7.7 Hz), 7.70- 7.66 (1H, m),7.56-7.48 (2H, m), 7.43-7.38 (1H, m), 7.33-7.25 (2H, m), 7.15 (1H, s),2.37-2.29 (1H, m), 1.17-1.05 (2H, m), 0.85- 0.79 (1H, m), 0.72-0.65 (1H,m). 269

¹H-NMR (CDCl₃) δ: 7.63-7.59 (1H, m), 7.47 (2H, d, J = 8.1 Hz), 7.41-7.36(1H, m), 7.20-7.16 (1H, m), 6.87- 6.85 (1H, m), 6.58 (1H, dd, J = 8.5,2.0 Hz), 3.55-3.34 (3H, m), 2.97-2.91 (1H, m), 2.63 (1H, s), 2.48-2.38(1H, m), 2.20-2.12 (1H, m), 1.71-1.61 (1H, m), 1.15 (3H, d, J = 6.7 Hz).270

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.23 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H,dd, J = 8.3, 2.1 Hz), 4.46 (1H, t, J = 5.1 Hz), 4.04 (2H, t, J = 6.5Hz), 3.50-3.44 (2H, m), 1.82-1.73 (2H, m), 1.63- 1.54 (2H, m). 271

¹H-NMR (DMSO-D₆) δ: 8.07 (1H, d, J = 7.5 Hz), 7.65- 7.61 (1H, m),7.53-7.47 (1H, m), 7.37-7.33 (1H, m), 7.31 (1H, s), 7.20-7.18 (1H, m),7.03 (1H, d, J = 2.2 Hz), 3.74-3.68 (4H, m), 3.29-3.24 (4H, m), 1.23(9H, s). 272

¹H-NMR (CDCl₃) δ: 8.47 (1H, d, J = 7.7 Hz), 7.73-7.70 (1H, m), 7.65 (2H,s), 7.57-7.52 (1H, m), 7.46- 7.42 (1H, m), 2.70 (1H, s).

TABLE 1-40 compound No. structural formula NMR 273

¹H-NMR (DMSO-D₆) δ: 8.53- 8.47 (1H, m), 7.82-7.75 (1H, m), 7.72 (1H, d,J = 7.5 Hz), 7.67 (1H, d, J = 7.5 Hz), 7.50-7.46 (1H, m), 7.46-7.42 (1H,m), 7.36- 7.31 (2H, m), 7.29 (1H, s), 7.28-7.23 (1H, m), 6.76 (1H, d, J= 7.5 Hz), 2.60 (3H, s). 274

¹H-NMR (DMSO-D₆) δ: 7.90- 7.86 (1H, m), 7.79-7.68 (3H, m), 7.59-7.54(1H, m), 7.48-7.41 (2H, m), 7.39 (1H, s), 2.77 (3H, s). 275

¹H-NMR (DMSO-D₆) δ: 7.77- 7.74 (1H, m), 7.71-7.67 (1H, m), 7.54 (1H, dd,J = 7.7, 1.3 Hz), 7.51-7.47 (1H, m), 7.47-7.39 (2H, m), 7.39 (1H, s),7.33 (1H, s), 7.25 (1H, dd, J = 6.5, 2.1 Hz), 2.55 (3H, s). 276

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.23 (2H, m), 7.00-6.97 (1H, m), 4.07-4.02 (2H, m), 2.69 (1H,s), 1.92-1.81 (1H, m), 1.74-1.68 (2H, m), 1.00-0.96 (6H, m). 277

¹H-NMR (DMSO-D₆) δ: 13.15 (1H, br s), 7.99 (1H, br s), 7.70-7.58 (3H,m), 7.41-7.27 (4H, m), 7.25- 7.20 (2H, m). 278

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.40 (1H,m), 7.30- 7.23 (2H, m), 7.00-6.97 (1H, m), 4.04-3.99 (2H, m), 2.69 (1H,br s), 1.86-1.78 (2H, m), 1.52-1.35 (4H, m), 0.98-0.92 (3H, m). 279

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.24 (2H, m), 7.01-6.98 (1H, m), 3.66 (2H, s), 2.70 (1H, s),1.07 (9H, s).

TABLE 1-41 compound No. structural formula NMR 280

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(1H, m), 7.33 (1H, br s), 7.32-7.27 (1H, m), 7.25-7.22 (1H, m),7.16-7.14 (1H, m), 7.08- 7.04 (1H, m), 6.78 (1H, br s), 4.03 (2H, t, J =6.3 Hz), 2.25 (2H, t, J = 7.2 Hz), 1.99-1.91 (2H, m). 281

¹H-NMR (DMSO-D₆) δ: 7.79 (1H, br s), 7.77-7.72 (2H, m), 7.61-7.57 (1H,m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.22 (1H, m), 7.16-7.13(1H, m), 7.08-7.04 (1H, m), 4.05- 3.99 (2H, m), 2.60-2.56 (3H, m),2.28-2.23 (2H, m), 2.01-1.92 (2H, m). 282

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.17-7.14 (1H, m),7.09-7.05 (1H, m), 4.06 (2H, t, J = 6.4 Hz), 2.97 (3H, s), 2.83 (3H, s),2.50-2.45 (2H, m), 2.00- 1.92 (2H, m). 283

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.58-7.52 (2H, m), 7.45-7.41 (1H,m), 7.45 (1H, s), 7.30-7.25 (1H, m), 7.25-7.23 (1H, m), 6.97 (1H, dd, J= 8.4, 2.4 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.07-4.01 (2H, m), 2.43- 2.37(2H, m), 1.92-1.78 (4H, m), 1.26 (3H, t, J = 7.2 Hz). 284

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.18-7.14 (1H, m),7.08-7.05 (1H, m), 4.60-4.56 (1H, m), 4.13- 4.07 (2H, m), 3.61-3.55 (2H,m), 1.94-1.85 (2H, m). 285

¹H-NMR (DMSO-D₆) δ: 8.72 (1H, dd, J = 4.9, 1.5 Hz), 8.64 (1H, d, J = 1.5Hz), 7.92-7.86 (1H, m), 7.61- 7.55 (2H, m), 7.30-7.27 (1H, m), 7.22 (1H,s), 7.21-7.14 (2H, m), 6.86 (1H, d, J = 2.4 Hz), 6.55 (1H, d, J = 6.8Hz), 3.75- 3.68 (4H, m), 3.29-3.24 (4H, m), 1.23 (9H, s). 286

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.68-7.63 (1H, m), 7.66 (1H, d, J =0.7 Hz), 7.60-7.57 (1H, m), 7.41 (1H, s), 7.40-7.34 (4H, m), 3.96 (3H,s).

TABLE 1-42 compound No. structural formula NMR 287

¹H-NMR (DMSO-D₆) δ: 13.07 (1H, br s), 7.78-7.73 (2H, m), 7.61-7.56 (1H,m), 7.49-7.43 (1H, m), 7.33- 7.28 (1H, m), 7.27-7.24 (1H, m), 7.15-7.13(1H, m), 7.06-7.02 (1H, m), 4.75 (2H, s). 288

¹H-NMR (DMSO-D₆) δ: 7.79- 7.74 (2H, m), 7.63 (1H, br s), 7.62-7.58 (1H,m), 7.49-7.44 (1H, m), 7.43 (1H, br s), 7.34-7.29 (1H, m), 7.27-7.22(2H, m), 7.10-7.06 (1H, m), 4.49 (2H, s). 289

¹H-NMR (DMSO-D₆) δ: 8.17- 8.11 (1H, m), 7.80-7.74 (2H, m), 7.62-7.58(1H, m), 7.49-7.45 (1H, m), 7.34- 7.28 (1H, m), 7.27-7.24 (2H, m),7.11-7.07 (1H, m), 4.53 (2H, s), 2.70-2.65 (3H, m). 290

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44(1H, m), 7.33-7.28 (1H, m), 7.26- 7.23 (1H, m), 7.17-7.14 (1H, m),7.06-7.01 (1H, m), 4.88 (2H, s), 3.02 (3H, s), 2.86 (3H, s). 291

¹H-NMR (DMSO-D₆) δ: 12.40 (1H, br s), 7.80-7.71 (2H, m), 7.62-7.56 (1H,m), 7.49-7.42 (1H, m), 7.34- 7.21 (2H, m), 7.15 (1H, s), 7.11-7.04 (1H,m), 4.28- 4.18 (2H, m), 2.77-2.69 (2H, m). 292

¹H-NMR (DMSO-D₆) δ: 7.78- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.23 (1H, s), 7.18-7.16 (1H, m), 7.07 (1H,dd, J = 8.4, 2.4 Hz), 4.89 (1H, t, J = 5.5 Hz), 4.07-4.03 (2H, m),3.77-3.72 (2H, m). 293

¹H-NMR (DMSO-D₆) δ: 7.60- 7.56 (2H, m), 7.54-7.50 (1H, m), 7.40-7.36(1H, m), 7.20-7.15 (1H, m), 7.08- 7.05 (1H, m), 6.83-6.80 1H, m),6.65-6.61 (1H, m), 3.98-3.88 (1H, m), 3.46- 3.39 (1H, m), 3.22-3.13 (1H,m), 2.11-1.94 (3H, m), 1.70 (1H, d, J = 42.9 Hz), 1.15 (3H, t, J = 6.8Hz).

TABLE 1-43 compound No. structural formula NMR 294

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.52 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.01 (2H, t, J = 6.5 Hz),2.70-2.70 (1H, m), 1.84-1.76 (2H, m), 1.53- 1.44 (2H, m), 1.39-1.32 (4H,m), 0.95-0.89 (3H, m). 295

¹H-NMR (DMSO-D₆) δ: 12.05 (1H, br s), 7.77-7.72 (2H, m), 7.60-7.57 (1H,m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.22 (1H, s), 7.16-7.14 (1H,m), 7.08- 7.05 (1H, m), 4.04 (2H, t, J = 5.9 Hz), 2.31 (2H, t, J = 7.2Hz), 1.80-1.63 (4H, m). 296

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.04 (2H, t, J = 6.4 Hz),3.70 (2H, t, J = 5.8 Hz), 2.79 (1H, s), 1.89-1.81 (2H, m), 1.71- 1.63(2H, m), 1.62-1.53 (2H, m), 1.32-1.20 (1H, m). 297

¹H-NMR (DMSO-D₆) δ: 7.94- 7.88 (2H, m), 7.68-7.61 (2H, m), 7.58-7.51(2H, m), 7.45-7.40 (1H, m), 7.35 (1H, br s), 4.81 (1H, t, J = 5.4 Hz),3.68-3.45 (4H, m), 3.00 (3H, br s). 298

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H,m), 7.30- 7.23 (2H, m), 6.98 (1H, dd, J = 8.4, 2.4 Hz), 4.03 (2H, t, J =6.4 Hz), 3.67 (2H, t, J = 6.4 Hz), 2.81 (1H, s), 1.87-1.79 (2H, m),1.66-1.58 (2H, m), 1.52- 1.41 (4H, m), 1.29-1.20 (1H, m). 299

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H,dd, J = 8.4, 2.4 Hz), 4.04 (2H, t, J = 6.3 Hz), 2.96 (3H, s), 2.81 (3H,s), 2.37 (2H, t, J = 7.3 Hz), 1.80-1.72 (2H, m), 1.70-1.62 (2H, m). 300

¹H-NMR (DMSO-D₆) δ: 9.38 (1H, s), 8.96 (2H, br s), 7.81-7.77 (1H, m),7.71- 7.67 (1H, m), 7.56-7.52 (1H, m), 7.45 (1H, dd, J = 7.7, 1.1 Hz),7.40-7.35 (1H, m), 7.37 (1H, s), 7.31-7.26 (1H, m), 6.71 (1H, d, J = 7.7Hz).

TABLE 1-44 compound No. structural formula NMR 301

¹H-NMR (DMSO-D₆) δ: 7.78- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.50-7.43(2H, m), 7.33-7.27 (1H, m), 7.25- 7.23 (1H, m), 7.16-7.13 (1H, m),7.08-7.04 (1H, m), 6.95 (1H, br s), 4.25-4.20 (2H, m), 2.59-2.53 (2H,m). 302

¹H-NMR (DMSO-D₆) δ: 7.98- 7.91 (1H, m), 7.77-7.72 (2H, m), 7.61-7.57(1H, m), 7.49-7.43 (1H, m), 7.33- 7.27 (1H, m), 7.25-7.23 (1H, m),7.15-7.12 (1H, m), 7.08-7.04 (1H, m), 4.24 (2H, t, J = 5.3 Hz), 2.63-2.60 (3H, m), 2.59-2.54 (2H, m). 303

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.08-7.04(1H, m), 4.25 (2H, t, J = 6.3 Hz), 3.01 (3H, s), 2.85 (3H, s), 2.82 (2H,t, J = 6.3 Hz). 304

¹H-NMR (CDCl₃) δ: 8.03-7.87 (1H, m), 7.84-7.64 (4H, m), 7.54-7.48 (1H,m), 7.45- 7.39 (1H, m), 5.01-4.86 (1H, m), 4.59-4.09 (1H, m), 3.88-3.47(4H, m), 2.77- 2.61 (1H, m), 2.44-2.21 (1H, m). 305

¹H-NMR (DMSO-D₆) δ: 7.79- 7.71 (3H, m), 7.61-7.57 (1H, m), 7.49-7.43(1H, m), 7.33-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.17-7.14 (1H, m),7.09-7.04 (1H, m), 4.06-4.00 (2H, m), 2.59- 2.55 (3H, m), 2.16-2.11 (2H,m), 1.76-1.62 (4H, m). 306

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43(1H, m), 7.33-7.26 (2H, m), 7.24- 7.22 (1H, m), 7.17-7.14 (1H, m),7.09-7.04 (1H, m), 6.73 (1H, br s), 4.06-4.01 (2H, m), 2.16-2.10 (2H,m), 1.78-1.63 (4H, m). 307

¹H-NMR (DMSO-D₆) δ: 7.94- 7.90 (2H, m), 7.68-7.64 (1H, m), 7.60-7.47(3H, m), 7.45-7.40 (1H, m), 7.36 (1H, s), 3.50-3.35 (1H, m), 3.26-3.09(1H, m), 3.01- 2.88 (3H, m), 1.71-1.47 (2H, m), 1.00-0.59 (3H, m).

TABLE 1-45 compound No. structural formula NMR 308

¹H-NMR (DMSO-D₆) δ: 7.94- 7.90 (2H, m), 7.68-7.64 (1H, m), 7.60-7.49(3H, m), 7.45-7.40 (1H, m), 7.36 (1H, s), 3.53-3.11 (2H, m), 3.01-2.89(3H, m), 1.65- 0.68 (7H, m). 309

¹H-NMR (DMSO-D₆) δ: 7.78 (1H, dd, J = 4.9, 3.1 Hz), 7.70-7.64 (2H, m),7.65 (1H, dd, J = 4.2, 2.1 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.37-7.21 (4H,m), 7.26 (1H, s), 6.89 (1H, d, J = 7.3 Hz). 310

¹H-NMR (DMSO-D₆) δ: 8.62- 8.57 (1H, m), 8.17-8.14 (1H, m), 8.06-8.01(1H, m), 7.97-7.92 (2H, m), 7.70- 7.66 (1H, m), 7.58-7.52 (1H, m),7.48-7.43 (1H, m), 7.37-7.34 (1H, m), 4.78- 4.72 (1H, m), 3.58-3.49 (2H,m), 3.43-3.27 (2H, m). 311

¹H-NMR (DMSO-D₆) δ: 8.63- 8.57 (1H, m), 8.16-8.11 (1H, m), 8.04-7.99(1H, m), 7.97-7.91 (2H, m), 7.70- 7.65 (1H, m), 7.58-7.52 (1H, m),7.48-7.42 (1H, m), 7.37-7.33 (1H, m), 4.51- 4.47 (1H, m), 3.52-3.45 (2H,m), 3.39-3.27 (2H, m), 1.75-1.67 (2H, m). 312

¹H-NMR (DMSO-D₆) δ: 8.62 (1H, t, J = 5.1 Hz), 8.16- 8.13 (1H, m),8.04-8.00 (1H, m), 7.96-7.91 (2H, m), 7.70-7.65 (1H, m), 7.57- 7.53 (1H,m), 7.47-7.42 (1H, m), 7.37-7.35 (1H, m), 4.44-4.40 (1H, m), 3.46- 3.40(2H, m), 3.35-3.24 (2H, m), 1.62-1.53 (2H, m), 1.52-1.44 (2H, m). 313

¹H-NMR (CD₃OD) δ: 7.81 (1H, d, J = 7.1 Hz), 7.69 (1H, d, J = 7.3 Hz),7.57 (1H, d, J = 7.5 Hz), 7.49-7.43 (1H, m), 7.37-7.27 (3H, m), 2.56(3H, s). 314

¹H-NMR (DMSO-D₆) δ: 12.86 (1H, br s), 7.99-7.76 (4H, m), 7.67 (1H, d, J= 7.1 Hz), 7.58-7.52 (1H, m), 7.48-7.35 (2H, m), 5.20- 5.04 (0.3H, m),4.81-4.72 (0.7H, m), 4.47-3.91 (2H, m), 2.81-2.57 (1H, m), 2.29-2.05(1H, m).

TABLE 1-46 compound No. structural formula NMR 315

¹H-NMR (DMSO-D₆) δ: 8.62 (1H, t, J = 5.6 Hz), 8.15- 8.13 (1H, m), 8.01(1H, dd, J = 7.9, 1.8 Hz), 7.96-7.91 (2H, m), 7.69-7.66 (1H, m),7.57-7.52 (1H, m), 7.46- 7.42 (1H, m), 7.34 (1H, s), 3.36-3.27 (2H, m),1.15 (3H, t, J = 7.2 Hz). 316

¹H-NMR (DMSO-D₆) δ: 8.60 (1H, t, J = 5.5 Hz), 8.15- 8.13 (1H, m), 8.02(1H, dd, J = 7.9, 1.5 Hz), 7.96-7.91 (2H, m), 7.69-7.66 (1H, m),7.57-7.52 (1H, m), 7.46- 7.42 (1H, m), 7.34 (1H, s), 3.28-3.21 (2H, m),1.61- 1.51 (2H, m), 0.91 (3H, t, J = 7.5 Hz). 317

¹H-NMR (DMSO-D₆) δ: 7.80- 7.78 (1H, m), 7.76 (1H, d, J = 7.7 Hz),7.62-7.59 (1H, m), 7.52-7.45 (2H, m), 7.40-7.26 (6H, m), 7.23- 7.17 (1H,m), 7.18 (1H, s), 4.03 (2H, s). 318

¹H-NMR (DMSO-D₆) δ: 11.99 (1H, br s), 7.76-7.72 (2H, m), 7.60-7.56 (1H,m), 7.47-7.43 (1H, m), 7.31- 7.27 (1H, m), 7.21 (1H, s), 7.15-7.13 (1H,m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 4.02 (2H, t, J = 6.6 Hz), 2.24 (2H,t, J = 7.3 Hz), 1.78-1.70 (2H, m), 1.62- 1.53 (2H, m), 1.49-1.42 (2H,m). 319

¹H-NMR (DMSO-D₆) δ: 7.94- 7.90 (2H, m), 7.68-7.64 (1H, m), 7.60-7.48(3H, m), 7.45-7.41 (1H, m), 7.37 (1H, s), 4.46-4.34 (1H, m), 3.53-3.14(4H, m), 3.01- 2.86 (3H, m), 1.69-1.13 (4H, m). 320

¹H-NMR (DMSO-D₆) δ: 8.13 (3H, br s), 7.80 (1H, d, J = 8.3 Hz), 7.77 (1H,d, J = 7.4 Hz), 7.62-7.59 (1H, m), 7.50-7.45 (1H, m), 7.34- 7.30 (1H,m), 7.24-7.22 (1H, m), 7.13 (1H, dd, J = 8.5, 2.4 Hz), 4.24 (2H, t, J =5.1 Hz), 3.57 (1H, s), 3.25 (2H, br s). 321

¹H-NMR (DMSO-D₆) δ: 8.91 (2H, br s), 7.81 (1H, d, J = 8.3 Hz), 7.79-7.76(1H, m), 7.63-7.59 (1H, m), 7.50-7.45 (1H, m), 7.34- 7.30 (1H, m),7.24-7.23 (1H, m), 7.14 (1H, dd, J = 8.3, 2.3 Hz), 4.31 (2H, t, J = 5.1Hz), 3.39-3.34 (2H, m), 2.65 (3H, br s).

TABLE 1-47 compound No. structural formula NMR 322

¹H-NMR (DMSO-D₆) δ: 7.76- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.17-7.15 (1H, m), 7.08 (1H,dd, J = 8.4, 2.4 Hz), 4.11 (2H, t, J = 5.7 Hz), 2.64 (2H, t, J = 5.7Hz), 2.23 (6H, s). 323

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H,m), 7.31- 7.23 (2H, m), 6.98 (1H, dd, J = 8.3, 2.6 Hz), 5.00 (1H, br s),4.08 (2H, t, J = 5.1 Hz), 3.59-3.52 (2H, m), 2.87 (1H, br s), 1.46 (9H,s). 324

¹H-NMR (CDCl₃) δ: 7.68-7.65 (1H, m), 7.58-7.54 (2H, m), 7.46-7.42 (1H,m), 7.31- 7.21 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 4.15 (2H, br s),3.65-3.59 (2H, m), 2.99 (3H, br s), 2.96-2.90 (1H, m), 1.46 (9H, s). 325

¹H-NMR (CDCl₃) δ: 7.68-7.65 (1H, m), 7.58-7.55 (2H, m), 7.47-7.42 (1H,m), 7.32- 7.27 (1H, m), 7.27-7.24 (1H, m), 6.98 (1H, dd, J = 8.3, 2.3Hz), 5.94 (1H, br s), 4.09 (2H, t, J = 5.0 Hz), 3.70-3.65 (2H, m), 3.03(1H, br s), 2.01 (3H, s). 326

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.53 (2H, m), 7.47-7.41 (1H,m), 7.32- 7.21 (2H, m), 6.97 (1H, dd, J = 8.3, 2.6 Hz), 4.19-4.15 (2H,m), 3.80-3.68 (2H, m), 3.26 (0.7H, s), 3.22 (0.3H, s), 3.17 (2.1H, s),3.00 (0.9H, s), 2.18 (0.9H, s), 2.08 (2.1H, s). 327

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.5 Hz), 7.68- 7.65 (1H, m),7.62-7.49 (3H, m), 7.45-7.41 (1H, m), 7.38 (1H, s), 4.55-4.38 (1H, m),3.57-3.21 (4H, m), 3.01-2.91 (3H, m), 1.81- 1.63 (2H, m). 328

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.5 Hz), 7.83 (1H, s), 7.79 (1H,s), 7.77-7.73 (1H, m), 7.66- 7.61 (1H, m), 7.59-7.52 (2H, m), 4.67 (1H,t, J = 5.4 Hz), 4.56-4.45 (1H, m), 4.42-4.36 (1H, m), 4.33- 4.15 (2H,m), 3.94-3.86 (1H, m), 3.54-3.48 (2H, m), 3.46-3.40 (2H, m).

TABLE 1-48 compound No. structural formula NMR 329

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.5 Hz), 7.83 (1H, s), 7.79-7.73(2H, m), 7.66-7.53 (3H, m), 4.58- 4.41 (2H, m), 4.32-4.23 (1H, m),4.18-4.10 (1H, m), 3.83-3.74 (1H, m), 2.86 (3H, s), 2.86 (3H, s). 330

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.7 Hz), 7.83 (1H, s), 7.79-7.73(2H, m), 7.66-7.61 (1H, m), 7.59- 7.52 (1H, m), 7.58 (1H, s), 4.83 (1H,t, J = 5.3 Hz), 4.41-4.32 (1H, m), 4.12- 4.03 (2H, m), 3.85-3.78 (1H,m), 3.56 (2H, t, J = 5.7 Hz), 2.80-2.69 (1H, m). 331

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.42(1H, m), 7.32-7.26 (1H, m), 7.22 (1H, s), 7.17-7.14 (1H, m), 7.06 (1H,dd, J = 8.5, 2.4 Hz), 4.09 (2H, t, J = 6.4 Hz), 2.71 (2H, t, J = 6.8Hz), 1.85-1.75 (2H, m). 332

¹H-NMR (DMSO-D₆) δ: 8.74 (1H, br s), 7.79-7.74 (2H, m), 7.62-7.58 (1H,m), .49-7.44 (1H, m), 7.33- 7.28 (1H, m), 7.25 (1H, s), 7.19-7.17 (1H,m), 7.08 (1H, dd, J = 8.3, 2.6 Hz), 4.13 (2H, t, J = 6.0 Hz), 3.08 (2H,br s), 2.58 (3H, br s), 2.14-2.06 (2H, m). 333

¹H-NMR (CDCl₃) δ: 7.71-7.67 (1H, m), 7.55 (2H, d, J = 8.3 Hz), 7.44-7.38(1H, m), 7.30-7.23 (2H, m), 6.95 (1H, dd, J = 8.3, 2.3 Hz), 3.87-3.80(2H, m), 2.18- 2.11 (2H, m), 1.88 (6H, s), 1.81-1.70 (2H, m). 334

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.58-7.52 (2H, m), 7.47-7.40 (1H,m), 7.34- 7.23 (2H, m), 7.00-6.95 (1H, m), 4.07-4.05 (2H, m), 3.66-3.43(2H, m), 3.03 (1.7H, s), 2.94 (1.3H, s), 2.10-2.00 (2H, m), 2.08 (1.3H,s), 2.05 (1.8H, s). 335

¹H-NMR (DMSO-D₆) δ: 9.40 (1H, s), 8.99 (2H, br s), 7.78-7.75 (1H, m),7.72- 7.68 (1H, m), 7.63 (1H, d, J = 2.0 Hz), 7.58 (1H, s), 7.43-7.38(1H, m), 7.34- 7.29 (1H, m), 6.68 (1H, d, J = 7.5 Hz).

TABLE 1-49 compound No. structural formula NMR 336

¹H-NMR (DMSO-D₆) δ: 8.59 (3H, br s), 7.81 (1H, d, J = 7.9 Hz), 7.75-7.67(2H, m), 7.60-7.54 (2H, m), 7.50-7.44 (2H, m), 7.34 (1H, s), 4.53 (1H,d, J = 15.0 Hz), 4.46 (1H, d, J = 15.0 Hz). 337

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88- 7.86 (1H, m),7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.57-7.53 (1H, m), 7.47- 7.43 (1H,m), 7.41 (1H, s), 5.02-4.89 (1H, m), 4.55- 4.06 (5H, m), 3.75-3.61 (1H,m), 3.47-3.12 (4H, m), 2.00-1.70 (2H, m). 338

¹H-NMR (DMSO-D₆) δ: 8.56 (1H, t, J = 5.6 Hz), 8.01- 7.98 (1H, m), 7.91(1H, d, J = 7.7 Hz), 7.84-7.82 (1H, m), 7.73-7.69 (1H, m), 7.59-7.54(1H, m), 7.48- 7.43 (1H, m), 7.27 (1H, s), 4.40 (1H, t, J = 5.1 Hz),3.46-3.40 (2H, m), 3.30- 3.25 (2H, m), 2.68 (3H, s), 1.61-1.53 (2H, m),1.51- 1.43 (2H, m). 339

¹H-NMR (DMSO-D₆) δ: 8.34- 8.30 (1H, m), 7.83-7.80 (1H, m), 7.77-7.73(2H, m), 7.65-7.61 (1H, m), 7.59- 7.53 (2H, m), 5.77 (1H, d, J = 6.2Hz), 4.56-4.42 (2H, m), 4.34-4.24 (1H, m), 4.15-4.02 (1H, m), 3.87- 3.77(1H, m). 340

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.41 (1H,m), 7.32- 7.24 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 5.76 (1H, br s),4.10 (2H, t, J = 5.8 Hz), 3.51-3.42 (2H, m), 3.11 (1H, br s), 2.07-1.96(2H, m), 1.98 (3H, s). 341

¹H-NMR (DMSO-D₆) δ: 8.78 (1H, dd, J = 4.7, 1.7 Hz), 8.76-8.74 (1H, m),8.06- 7.99 (4H, m), 7.95-7.91 (2H, m), 7.75 (1H, d, J = 1.8 Hz),7.73-7.69 (1H, m), 7.63 (1H, dd, J = 7.6, 5.2 Hz), 7.49 (1H, s), 7.41-7.36 (1H, m), 7.31-7.26 (1H, m), 6.72 (1H, d, J = 7.7 Hz), 1.58 (9H, s).342

¹H-NMR (DMSO-D₆) δ: 9.00- 8.96 (1H, m), 8.91 (1H, dd, J = 5.2, 1.4 Hz),8.37-8.32 (1H, m), 8.11-8.05 (3H, m), 7.97-7.92 (2H, m), 7.91- 7.86 (1H,m), 7.84-7.81 (1H, m), 7.74-7.70 (1H, m), 7.52 (1H, br s), 7.43-7.38(1H, m), 7.32-7.27 (1H, m), 6.79 (1H, d, J = 7.5 Hz).

TABLE 1-50 compound No. structural formula NMR 343

¹H-NMR (DMSO-D₆) δ: 8.15- 8.13 (1H, m), 8.08-8.05 (1H, m), 7.85 (1H, d,J = 1.5 Hz), 7.73-7.68 (1H, m), 7.67 (1H, d, J = 0.9 Hz), 7.49-7.35 (4H,m), 3.97 (3H, s), 3.90 (3H, s). 344

¹H-NMR (DMSO-D₆) δ: 13.24 (1H, br s), 8.14-8.12 (1H, m), 8.06-8.05 (1H,m), 7.83 (1H, d, J = 1.6 Hz), 7.72- 7.68 (1H, m), 7.66 (1H, d, J = 0.7Hz), 7.47-7.36 (4H, m), 3.97 (3H, s). 345

¹H-NMR (DMSO-D₆) δ: 8.62 (1H, t, J = 5.7 Hz), 8.10 (1H, s), 8.02 (1H,s), 7.82 (1H, d, J = 1.5 Hz), 7.72- 7.62 (1H, m), 7.65 (1H, s),7.44-7.30 (3H, m), 7.34 (1H, s), 4.40 (1H, t, J = 5.1 Hz), 3.98 (3H, s),3.44-3.39 (2H, m), 3.36- 3.19 (2H, m), 1.63-1.39 (4H, m). 346

¹H-NMR (DMSO-D₆) δ: 8.04- 8.00 (1H, m), 7.69-7.63 (2H, m), 7.62-7.58(1H, m), 7.43-7.30 (5H, m), 4.82 (1H, t, J = 5.3 Hz), 3.96 (3H, s),3.68-3.59 (1H, m), 3.56-3.48 (2H, m), 3.40- 3.33 (1H, m), 3.01 (3H, s).347

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.52 (1H, s), 7.49 (1H, s),7.36-7.21 (5H, m), 4.26 (2H, q, J = 7.3 Hz), 3.15 (1H, br s), 1.57 (3H,t, J = 7.3 Hz). 348

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43(1H, m), 7.33-7.23 (2H, m), 7.17- 7.15 (1H, m), 7.11-7.06 (1H, m),4.54-4.45 (1H, m), 4.23-4.07 (4H, m), 3.73- 3.62 (2H, m), 3.00 (1.6H,s), 2.94 (1.4H, s). 349

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.5 Hz), 7.84- 7.82 (1H, m), 7.78(1H, d, J = 1.3 Hz), 7.77-7.73 (1H, m), 7.65-7.61 (1H, m), 7.58-7.53(1H, m), 7.57 (1H, s), 7.35 (1H, br s), 7.26 (1H, br s), 4.56-4.48 (1H,m), 4.45-4.39 (1H, m), 4.32-4.23 (2H, m), 4.01- 3.93 (1H, m), 3.84 (2H,s).

TABLE 1-51 compound No. structural formula NMR 350

¹H-NMR (DMSO-D₆) δ: 7.91 (1H, d, J = 7.7 Hz), 7.73- 7.69 (2H, m),7.59-7.54 (2H, m), 7.48-7.44 (1H, m), 7.33 (1H, s), 5.76 (1H, d, J = 6.3Hz), 4.55-4.43 (2H, m), 4.31-4.23 (1H, m), 4.13-4.00 (1H, m), 3.87- 3.75(1H, m), 2.68 (3H, s). 351

¹H-NMR (DMSO-D₆) δ: 7.91 (1H, d, J = 7.7 Hz), 7.73- 7.69 (2H, m),7.59-7.54 (2H, m), 7.48-7.43 (1H, m), 7.33 (1H, s), 4.83 (1H, t, J = 5.4Hz), 4.38-4.31 (1H, m), 4.09-4.03 (2H, m), 3.82-3.78 (1H, m), 3.56 (2H,t, J = 5.7 Hz), 2.78- 2.70 (1H, m), 2.68 (3H, s). 352

¹H-NMR (DMSO-D₆) δ: 7.93- 7.90 (1H, m), 7.74-7.69 (2H, m), 7.60-7.54(2H, m), 7.48-7.44 (1H, m), 7.35 (1H, br s), 7.33 (1H, s), 7.26 (1H, brs), 4.54-4.45 (1H, m), 4.44-4.38 (1H, m), 4.31-4.21 (2H, m), 3.99- 3.92(1H, m), 3.83 (2H, s), 2.69 (3H, s). 353

¹H-NMR (DMSO-D₆) δ: 7.84- 7.79 (2H, m), 7.64-7.61 (1H, m), 7.56-7.54(1H, m), 7.52-7.48 (1H, m), 7.42- 7.35 (2H, m), 7.23 (1H, s), 3.79 (2H,s), 3.64 (3H, s). 354

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.69-7.65 (1H, m), 7.65 (1H, d, J =0.7 Hz), 7.60-7.59 (1H, m), 7.42- 7.35 (4H, m), 7.30 (1H, d, J = 1.4Hz), 3.96 (3H, s), 2.99 (6H, s). 355

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.83-7.81 (1H, m), 7.70-7.67 (1H, m),7.66 (1H, d, J = 0.7 Hz), 7.49 (1H, d, J = 1.6 Hz), 7.43- 7.36 (4H, m),4.38-4.32 (2H, m), 4.10-4.04 (2H, m), 3.97-(3H, s), 2.32-2.23 (2H, m).356

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.72-7.70 (1H, m), 7.69-7.65 (1H, m),7.66 (1H, d, J = 0.9 Hz), 7.43- 7.34 (5H, m), 3.96 (3H, s), 3.51-3.42(4H, m), 1.91- 1.81 (4H, m).

TABLE 1-52 compound No. structural formula NMR 357

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44(1H, m), 7.33-7.29 (1H, m), 7.27 (1H, s), 7.16-7.14 (1H, m), 7.07 (1H,dd, J = 8.3, 2.6 Hz), 4.88 (2H, s), 3.72 (3H, s). 358

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.64-7.57 (2H, m), 7.60 (1H, s), 7.41(1H, br s), 7.30-7.25 (3H, m), 7.24 (1H, s), 7.23-7.20 (1H, m), 6.84(1H, d, J = 2.6 Hz), 4.50 (2H, s), 3.96 (3H, s). 359

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.41 (1H,m), 7.32- 7.23 (2H, m), 6.97 (1H, dd, J = 8.5, 2.4 Hz), 4.17 (2H, t, J =5.3 Hz), 3.71-3.67 (2H, m), 3.59 (2H, t, J = 7.2 Hz), 3.11 (1H, br s),2.38 (2H, t, J = 8.3 Hz), 2.09-1.98 (2H, m). 360

¹H-NMR (DMSO-D₆) δ: 7.74 (2H, d, J = 8.3 Hz), 7.60- 7.57 (1H, m),7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m),7.03 (1H, dd, J = 8.3, 2.3 Hz), 4.79 (2H, s), 3.52-3.46 (2H, m), 3.36-3.31 (2H, m), 1.95-1.87 (2H, m), 1.82-1.74 (2H, m). 361

¹H-NMR (DMSO-D₆) δ: 7.76- 7.73 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44(1H, m), 7.32-7.28 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.03 (1H,dd, J = 8.3, 2.6 Hz), 4.87 (2H, s), 3.46- 3.40 (4H, m), 1.63-1.52 (4H,m), 1.47-1.42 (2H, m). 362

¹H-NMR (DMSO-D₆) δ: 7.77- 7.73 (2H, m), 7.61-7.58 (1H, m), 7.48-7.44(1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.18-7.16 (1H, m), 7.05 (1H,dd, J = 8.5, 2.4 Hz), 4.91 (2H, s), 3.64- 3.55 (4H, m), 3.52-3.44 (4H,m). 363

¹H-NMR (DMSO-D₆) δ: 9.38 (1H, s), 8.96 (2H, br s), 7.67-7.62 (2H, m),7.43 (1H, br s), 7.40-7.37 (1H, m), 7.39 (1H, s), 7.31-7.22 (2H, m),7.05 (1H, d, J = 2.4 Hz), 6.64 (1H, d, J = 7.1 Hz), 4.56 (2H, s).

TABLE 1-53 compound No. structural formula NMR 364

¹H-NMR (DMSO-D₆) δ: 9.41 (1H, s), 9.01 (2H, br s), 8.31-8.28 (1H, m),8.01 (1H, d, J = 1.4 Hz), 7.77- 7.73 (1H, m), 7.63 (1H, s), 7.49-7.44(1H, m), 7.38- 7.33 (1H, m), 6.75 (1H, d, J = 7.9 Hz), 3.92 (3H, s). 365

¹H-NMR (DMSO-D₆) δ: 8.13 (1H, t, J = 5.6 Hz), 7.79- 7.74 (2H, m),7.62-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.29 (1H, m), 7.27- 7.23 (1H,m), 7.26 (1H, s), 7.09 (1H, dd, J = 8.3, 2.6 Hz), 4.73 (1H, t, J = 5.6Hz), 4.54 (2H, s), 3.47- 3.42 (2H, m), 3.25-3.20 (2H, m). 366

¹H-NMR (DMSO-D₆) δ: 7.76- 7.71 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.04-7.00(1H, m), 5.00 (0.6H, t, J = 5.1 Hz), 4.96 (1.2H, s), 4.88 (0.8H, s),4.69 (0.4H, t, J = 5.6 Hz), 3.61-3.57 (1.2H, m), 3.51- 3.47 (0.8H, m),3.42-3.33 (2H, m), 3.06 (1.2H, s), 2.86 (1.8H, s). 367

¹H-NMR (DMSO-D₆) δ: 13.42 (1H, br s), 9.41 (1H, s), 9.01 (2H, br s),8.30-8.28 (1H, m), 7.97 (1H, d, J = 1.4 Hz), 7.76-7.72 (1H, m), 7.58(1H, s), 7.48-7.43 (1H, m), 7.37-7.32 (1H, m), 6.74 (1H, d, J = 7.7 Hz).368

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, s), 9.00 (2H, br s), 7.78-7.76 (1H, m),7.74- 7.69 (1H, m), 7.52-7.51 (2H, m), 7.44-7.39 (1H, m), 7.35-7.30 (1H,m), 6.74 (1H, d, J = 7.7 Hz), 3.02 (6H, s). 369

¹H-NMR (DMSO-D₆) δ: 9.40 (1H, s), 8.99 (2H, br s), 7.99-7.97 (1H, m),7.74- 7.70 (1H, m), 7.66 (1H, d, J = 1.6 Hz), 7.54 (1H, s), 7.45-7.40(1H, m), 7.35- 7.31 (1H, m), 6.75 (1H, d, J = 7.7 Hz), 4.42-4.34 (2H,m), 4.13-4.05 (2H, m), 2.33- 2.24 (2H, m). 370

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, s), 9.00 (2H, br s), 7.89-7.86 (1H, m),7.74- 7.70 (1H, m), 7.62 (1H, d, J = 1.6 Hz), 7.51 (1H, s), 7.44-7.39(1H, m), 7.35- 7.30 (1H, m), 6.75 (1H, d, = 7.7 Hz), 3.56-3.44 (4H, m),1.93-1.81 (4H, m).

TABLE 1-54 compound No. structural formula NMR 371

¹H-NMR (DMSO-D₆) δ: 9.41 (1H, s), 9.02 (2H, br s), 8.67 (1H, t, J = 5.7Hz), 8.29-8.25 (1H, m), 7.95 (1H, d, J = 1.6 Hz), 7.75- 7.71 (1H, m),7.51 (1H, s), 7.45-7.40 (1H, m), 7.36- 7.31 (1H, m), 6.79 (1H, d, J =7.7 Hz), 4.41 (1H, t, J = 5.1 Hz), 3.45-3.39 (2H, m), 3.37-3.25 (2H, m),1.61-1.52 (2H, m), 1.51- 1.42 (2H, m). 372

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, s), 8.99 (2H, br s), 7.79-7.76 (1H, m),7.73- 7.69 (1H, m), 7.54-7.48 (2H, m), 7.43-7.38 (1H, m), 7.34-7.29 (1H,m), 6.75 (1H, d, J = 7.7 Hz), 4.88- 4.79 (1H, m), 3.67-3.60 (1H, m),3.57-3.50 (2H, m), 3.41-3.36 (1H, m), 3.06- 2.99 (3H, m). 373

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.82-7.79 (1H, m), 7.70-7.65 (1H, m),7.66 (1H, s), 7.48 (1H, d, J = 1.5 Hz), 7.43-7.36 (4H, m), 5.76 (1H, d,J = 5.7 Hz), 4.54-4.47 (2H, m), 4.31- 4.24 (1H, m), 4.09-4.03 (1H, m),3.97 (3H, s), 3.84-3.78 (1H, m). 374

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.84-7.81 (1H, m), 7.71-7.66 (1H, m),7.65 (1H, d, J = 0.7 Hz), 7.52- 7.48 (1H, m), 7.42-7.36 (4H, m), 4.83(1H, t, J = 5.4 Hz), 4.39-4.32 (1H, m), 4.12-4.02 (2H, m), 3.97 (3H, s),3.84-3.77 (1H, m), 3.55 (2H, t, J = 5.5 Hz), 2.79-2.69 (1H, m). 375

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.84-7.81 (1H, m), 7.70-7.66 (2H, m),7.51- 7.48 (1H, m), 7.44-7.35 (4H, m), 4.66 (1H, t, J = 5.4 Hz),4.55-4.46 (1H, m), 4.41-4.35 (1H, m), 4.32- 4.24 (1H, m), 4.19-4.13 (1H,m), 3.97 (3H, s), 3.92-3.86 (1H, m), 3.53- 3.48 (2H, m), 3.44-3.39 (2H,m). 376

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.72-7.65 (3H, m), 7.44-7.34 (5H, m),5.04- 4.95 (1H, m), 4.37-4.23 (1H, m), 3.96 (3H, s), 3.68-3.24 (4H, m),2.03- 1.88 (1H, m), 1.87-1.77 (1H, m).

TABLE 1-55 compound No. structural formula NMR 377

¹H-NMR (DMSO-D₆) δ: 8.25 (1H, s), 7.93 (1H, d, J = 0.7 Hz), 7.85-7.81(2H, m), 7.79-7.77 (1H, m), 7.71 (1H, dd, J = 7.9, 1.5 Hz), 7.65-7.61(1H, m), 7.52- 7.47 (1H, m), 7.39-7.34 (1H, m), 7.25 (1H, s), 3.88 (3H,s). 378

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 2.6 Hz), 7.79 (1H, d, J = 7.5 Hz),7.71- 7.66 (1H, m), 7.59-7.53 (2H, m), 7.49 (1H, s), 7.48-7.43 (1H, m),3.91 (3H, s). 379

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43(1H, m), 7.33-7.27 (1H, m), 7.24 (0.4H, s), 7.23 (0.6H, s), 7.18-7.14(1H, m), 7.11- 7.06 (1H, m), 4.85 (0.6H, t, J = 5.5 Hz), 4.68 (0.4H, t,J = 5.3 Hz), 4.20 (0.8H, t, J = 5.5 Hz), 4.12 (1.2H, t, J = 6.0 Hz),3.79-3.73 (0.8H, m), 3.69-3.63 (1.2H, m), 3.61-3.54 (1.2H, m), 3.51-3.38(2.8H, m), 2.10 (1.2H, s), 2.05 (1.8H, s). 380

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.49-7.43(1H, m), 7.32-7.21 (2H, m), 7.17- 7.13 (1H, m), 7.11-7.04 (1H, m),4.82-4.65 (1H, m), 3.71-3.62 (0.4H, m), 3.52- 3.39 (1.6H, m), 3.03(1.8H, s), 2.85 (0.6H, s), 2.84 (0.6H, s), 2.10 (1.2H, s), 1.96 (0.9H,s), 1.95 (0.9H, s), 1.29-1.21 (3H, m). 381

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43(1H, m), 7.33-7.27 (1H, m), 7.25- 7.22 (1H, m), 7.18-7.14 (1H, m),7.11-7.05 (1H, m), 4.92-4.79 (0.5H, m), 4.37- 4.25 (0.5H, m), 4.15-3.96(2H, m), 2.88 (1.5H, s), 2.70 (1.5H, s), 2.05 (1.5H, s), 2.00 (1.5H, s),1.25- 1.13 (3H, m). 382

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.28 (1H, m), 7.24 (1H, s), 7.16-7.12 (1H, m), 7.05-7.01(1H, m), 5.14- 5.10 (0.3H, m), 4.93 (0.6H, s), 4.80-4.77 (1.4H, m), 4.73(0.7H, t, J = 5.6 Hz), 4.12-4.04 (0.3H, m), 4.01- 3.94 (0.7H, m),3.55-3.26 (4H, m), 2.01-1.76 (4H, m).

TABLE 1-56 compound No. structural formula NMR 383

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.28 (1H, m), 7.24 (1H, s), 7.16-7.13 (1H, m), 7.05-7.01(1H, m), 5.14- 5.10 (0.3H, m), 4.95-4.91 (0.6H, m), 4.81-4.77 (1.4H, m),4.75-4.71 (0.7H, m), 4.12-4.04 (0.3H, m), 4.00- 3.94 (0.7H, m),3.55-3.26 (4H, m), 2.00-1.76 (4H, m). 384

¹H-NMR (DMSO-D₆) δ: 12.03 (1H, br s), 8.14 (1H, d, J = 7.7 Hz),7.68-7.64 (1H, m), 7.56-7.51 (1H, m), 7.42-7.38 (2H, m), 7.17- 7.14 (2H,m), 4.08 (2H, t, J = 6.3 Hz), 2.30 (2H, t, J = 7.2 Hz), 1.80-1.72 (2H,m), 1.71-1.64 (2H, m). 385

¹H-NMR (DMSO-D₆) δ: 8.15 (1H, d, J = 7.5 Hz), 7.69- 7.64 (2H, m),7.57-7.52 (1H, m), 7.48-7.39 (3H, m), 7.27-7.25 (1H, m), 7.15 (1H, d, J= 2.4 Hz), 4.55 (2H, s). 386

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.67-7.59 (2H, m), 7.61 (1H, s),7.41-7.26 (5H, m), 7.21 (1H, s), 4.03 (2H, d, J = 7.3 Hz), 2.27- 2.16(1H, m), 0.93 (3H, d, J = 2.0 Hz), 0.92 (3H, d, J = 2.0 Hz. 387

¹H-NMR (CDCl₃) δ: 8.20 (1H, d, J = 7.9 Hz), 7.70-7.65 (1H, m), 7.50-7.46(1H, m), 7.36-7.31 (1H, m), 7.20- 7.17 (1H, m), 6.95 (1H, d, J = 2.2Hz), 4.02 (2H, t, J = 6.4 Hz), 3.68 (2H, t, J = 6.3 Hz), 2.88 (1H, brs), 1.88-1.80 (2H, m), 1.69- 1.51 (4H, m). 388

¹H-NMR (CDCl₃) δ: 8.22-8.17 (1H, m), 7.71-7.66 (1H, m), 7.51-7.45 (1H,m), 7.37- 7.30 (1H, m), 7.20-7.16 (1H, m), 6.95-6.92 (1H, m), 4.16-4.09(2H, m), 3.90 (0.7H, br s), 3.77 (0.3H, br s), 3.73-3.61 (2H, m), 3.13(2.2H, s), 2.96 (0.8H, s), 2.14 (0.8H, s), 2.03 (2.2H, s). 389

¹H-NMR (DMSO-D₆) δ: 7.75 (2H, d, J = 8.3 Hz), 7.61- 7.57 (1H, m),7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.18-7.15 (1H, m),7.04 (1H, dd, J = 8.5, 2.4 Hz), 5.07 (0.5H, d, J = 3.7 Hz), 4.96 (0.5H,d, J = 3.2 Hz), 4.81 (1.0H, s), 4.76 (1.0H, s), 4.36 (0.5H, d, J = 20.4Hz), 4.27 (0.5H, d, J = 18.3 Hz), 3.65-3.53 (1.5H, m), 3.49- 3.27 (2.5H,m), 2.01-1.92 (0.5H, m), 1.91-1.81 (1.0H, m), 1.79-1.71 (0.5H, m).

TABLE 1-57 compound No. structural formula NMR 390

¹H-NMR (DMSO-D₆) δ: 7.74 (2H, d, J = 8.1 Hz), 7.60- 7.56 (1H, m),7.47-7.43 (1H, m), 7.32-7.27 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m),7.03 (1H, dd, J = 8.5, 2.4 Hz), 5.06 (0.5H, d, J = 3.7 Hz), 4.96 (0.5H,d, J = 3.2 Hz), 4.80 (1.0H, s), 4.75 (1.0H, s), 4.38- 4.33 (0.5H, m),4.28-4.24 (0.5H, m), 3.64-3.52 (1.5H, m), 3.48-3.23 (2.5H, m), 1.99-1.91(0.5H, m), 1.90- 1.80 (1.0H, m), 1.78-1.69 (0.5H, m). 391

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44(1H, m), 7.33-7.28 (1H, m), 7.26 (1H, s), 7.16-7.14 (1H, m), 7.04 (1H,dd, J = 8.3, 2.6 Hz), 4.64 (2H, s), 4.26 (2H, t, J = 8.5 Hz), 3.92 (2H,t, J = 7.8 Hz), 2.30- 2.20 (2H, m). 392

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, s), 7.73-7.63 (2H, m), 7.65 (1H, s),7.43-7.32 (5H, m), 4.82-4.76 (1H, m), 4.21-4.12 (1H, m), 3.96 (3H, s),3.61-3.55 (2H, m), 3.51--3.44 (1H, m), 3.41- 3.34 (1H, m), 2.02-1.83(3H, m), 1.77-1.64 (1H, m). 393

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.73-7.63 (2H, m), 7.65 (1H, s),7.43-7.32 (5H, m), 4.82-4.75 (1H, m), 4.21-4.12 (1H, m), 3.96 (3H, s),3.61-3.54 (2H, m), 3.51-3.44 (1H, m), 3.43- 3.34 (1H, m), 2.01-1.82 (3H,m), 1.78-1.66 (1H, m). 394

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.72-7.64 (3H, m), 7.42-7.34 (5H, m),4.73- 4.62 (1H, m), 3.96 (3H, s), 3.63-3.24 (6H, m), 2.39- 2.26 (1H, m),2.00-1.86 (1H, m), 1.71-1.60 (1H, m). 395

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.57-7.51 (2H, m), 7.46-7.40 (1H,m), 7.30- 7.23 (2H, m), 6.97 (1H, dd, J = 8.3, 2.3 Hz), 4.04 (2H, t, J =6.2 Hz), 3.52-3.38 (5H, m), 2.36-2.29 (2H, m), 2.06-1.95 (4H, m).

TABLE 1-58 compound No. structural formula NMR 396

¹H-NMR (DMSO-D₆) δ: 7.77- 7.73 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44(1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m), 7.03 (1H,dd, J = 8.3, 2.6 Hz), 4.91 (1H, d, J = 13.9 Hz), 4.86 (1H, d, J = 15.5Hz), 4.78 (1H, d, J = 3.7 Hz), 3.92-3.84 (1H, m), 3.76-3.65 (2H, m),3.25- 3.15 (1H, m), 3.12-3.01 (1H, m), 1.83-1.66 (2H, m), 1.47-1.35 (1H,m), 1.32- 1.21 (1H, m). 397

¹H-NMR (DMSO-D₆) δ: 7.77- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44(1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.16-7.13 (1H, m), 7.04 (1H,dd, J = 8.3, 2.3 Hz), 4.95-4.81 (2H, m), 4.52 (1H, t, J = 5.1 Hz),4.38-4.29 (1H, m), 3.92- 3.83 (1H, m), 3.26 (2H, t, J = 5.6 Hz),3.07-2.97 (1H, m), 2.63-2.54 (1H, m), 1.76- 1.58 (3H, m), 1.21-1.07 (1H,m), 1.03-0.90 (1H, m). 398

¹H-NMR (CDCl₃) δ: 8.15 (1H, d, J = 2.2 Hz), 7.81 (1H, d, J = 7.5 Hz),7.72 (1H, d, J = 7.5 Hz), 7.53-7.47 (2H, m), 7.43-7.38 (1H, m),4.18-4.03 (2H, m), 3.76- 3.67 (3H, m), 3.15 (2.3H, s), 2.98 (0.7H, s),2.16 (0.7H, s), 2.06 (2.3H, s). 399

¹H-NMR (CDCl₃) δ: 8.16-8.12 (1H, m), 7.86-7.81 (1H, m), 7.74-7.69 (1H,m), 7.56- 7.48 (1H, m), 7.48-7.38 (2H, m), 4.27-4.12 (4H, m), 3.89-3.49(4H, m), 3.09 (0.7H, s), 3.04 (2.3H, s). 400

¹H-NMR (DMSO-D₆) δ: 7.76- 7.71 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44(1H, m), 7.30 (1H, d, J = 18.6 Hz), 7.24 (1H, s), 7.16-7.13 (1H, m),7.01 (1H, dd, J = 8.5, 2.4 Hz), 5.02 (1H, t, J = 5.1 Hz), 4.97 (2H, s),4.71 (1H, t, J = 5.4 Hz), 3.63-3.57 (2H, m), 3.53- 3.32 (6H, m). 401

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.52 (2H, m), 7.45-7.40 (1H,m), 7.30- 7.25 (2H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.05 (2H, t, J =6.2 Hz), 3.74 (1H, s), 3.62-3.54 (1H, m), 3.47-3.39 (1H, m), 3.34- 3.27(2H, m), 2.33-2.28 (2H, m), 2.06-1.99 (2H, m), 1.82-1.71 (4H, m). 402

¹H-NMR (DMSO-D₆) δ: 12.39 (1H, br s), 7.83 (1H, d, J = 7.7 Hz), 7.79(1H, d, J = 7.9 Hz), 7.65-7.61 (1H, m), 7.56-7.53 (1H, m), 7.52- 7.47(1H, m), 7.41-7.35 (2H, m), 7.24 (1H, s), 3.67 (2H, s).

TABLE 1-59 compound No. structural formula NMR 403

¹H-NMR (DMSO-D₆) δ: 7.81 (1H, d, J = 7.5 Hz), 7.77 (1H, d, J = 7.7 Hz),7.64- 7.60 (1H, m), 7.58-7.52 (2H, m), 7.51-7.46 (1H, m), 7.41-7.34 (2H,m), 7.22 (1H, s), 6.92 (1H, br s), 3.47 (1H, d, J = 14.1 Hz), 3.43 (1H,d, J = 14.3 Hz). 404

¹H-NMR (CDCl₃) δ: 8.39-8.36 (1H, m), 7.69-7.65 (1H, m), 7.52-7.47 (1H,m), 7.37- 7.32 (1H, m), 7.26 (2H, s), 7.23-7.21 (1H, m), 7.14 (1H, d, J= 2.4 Hz), 4.09 (2H, t, J = 6.1 Hz), 2.61 (2H, t, J = 7.2 Hz), 2.20-2.12 (2H, m). 405

¹H-NMR (DMSO-D₆) δ: 7.80 (1H, d, J = 7.5 Hz), 7.74 (1H, d, J = 7.7 Hz),7.64- 7.59 (1H, m), 7.51-7.45 (2H, m), 7.38-7.32 (2H, m), 7.18 (1H, s),4.68 (1H, t, J = 5.1 Hz), 3.64 (2H, dt, J = 6.8, 5.1 Hz), 2.80 (2H, t, J= 6.8 Hz). 406

¹H-NMR (CDCl₃) δ: 9.20 (1H, s), 8.98-7.98 (2H, m), 7.72-7.69 (1H, m),7.42- 7.39 (1H, m), 7.25-7.21 (1H, m), 7.11-7.07 (1H, m), 6.69 (1H, d, J= 2.3 Hz), 6.46 (1H, d, J = 7.9 Hz), 4.48 (1H, s), 4.10-4.04 (2H, m),3.70 (2H, t, J = 6.1 Hz), 1.90-1.83 (2H, m), 1.71-1.54 (4H, m), 1.41(1H, br s). 407

¹H-NMR (CDCl₃) δ: 7.68-7.63 (1H, m), 7.54 (1H, d, J = 0.7 Hz), 7.49 (1H,s), 7.25-7.21 (4H, m), 6.78 (1H, d, J = 2.3 Hz), 4.04 (2H, t, J = 6.4Hz), 4.00 (3H, s), 3.69 (2H, t, J = 6.3 Hz), 3.24 (1H, br s), 1.89-1.81(2H, m), 1.70-1.52 (4H, m), 1.34 (1H, br s). 408

¹H-NMR (DMSO-D₆) δ: 8.15 (1H, d, J = 7.7 Hz), 7.69- 7.65 (1H, m),7.57-7.52 (1H, m), 7.44 (1H, s), 7.43-7.39 (1H, m), 7.21 (1H, d, J = 2.2Hz), 7.20- 7.18 (1H, m), 4.24 (2H, t, J = 5.4 Hz), 3.50 (2H, t, J = 5.4Hz), 2.95 (3H, s), 2.89 (3H, s). 409

¹H-NMR (DMSO-D₆) δ: 8.15 (1H, d, J = 7.7 Hz), 7.68- 7.64 (1H, m),7.56-7.52 (1H, m), 7.46-7.38 (2H, m), 7.20-7.16 (2H, m), 4.53 (0.4H, t,J = 5.4 Hz), 4.48 (0.6H, t, J = 5.5 Hz), 4.26-4.17 (3H, m), 4.09 (1H, d,J = 5.5 Hz), 3.70 (1.1H, t, J = 5.7 Hz), 3.64 (0.9H, t, J = 5.1 Hz),2.99 (1.6H, s), 2.93 (1.4H, s). 410

¹H-NMR (DMSO-D₆) δ: 8.14 (1H, d, J = 7.7 Hz), 7.68- 7.63 (1H, m),7.56-7.51 (1H, m), 7.46-7.38 (2H, m), 7.33 (1H, br s), 7.16 (2H, s),6.79 (1H, br s), 4.07 (2H, t, J = 6.4 Hz), 2.24 (2H, t, J = 7.4 Hz),1.98- 1.90 (2H, m).

TABLE 1-60 compound No. structural formula NMR 411

¹H-NMR (CDCl₃) δ: 7.73-7.67 (2H, m), 7.59 (1H, s), 7.57 (1H, s),7.37-7.23 (5H, m), 4.36-4.32 (2H, m), 4.13- 4.06 (2H, m), 3.07 (1H, brs), 2.96 (1H, br s). 412

¹H-NMR (CDCl₃) δ: 7.68-7.63 (1H, m), 7.59 (1H, s), 7.50 (1H, s),7.28-7.21 (4H, m), 6.77 (1H, d, J = 2.6 Hz), 4.16 (2H, t, J = 5.2 Hz),4.02 (3H, s), 3.71-3.66 (2H, m), 3.62-3.56 (2H, m), 3.15 (1H, br s),2.40-2.35 (2H, m), 2.08-1.99 (2H, m). 413

¹H-NMR (DMSO-D₆) δ: 7.78- 7.72 (2H, m), 7.65-7.56 (2H, m), 7.48-7.43(1H, m), 7.32-7.27 (2H, m), 7.24 (1H, d, J = 4.6 Hz), 7.20- 7.16 (1H,m), 7.05-7.01 (1H, m), 4.71-4.64 (1H, m), 1.49-1.44 (3H, m). 414

¹H-NMR (CDCl₃) δ: 7.93-7.91 (1H, m), 7.83-7.79 (1H, m), 7.61 (1H, d, J =0.7 Hz), 7.53 (1H, d, J = 1.6 Hz), 7.47-7.45 (1H, m), 7.40- 7.33 (2H,m), 7.29-7.25 (1H, m), 6.20 (1H, br s), 4.10-3.97 (2H, m), 4.04 (3H, s),3.25-3.18 (2H, m). 415

¹H-NMR (CDCl₃) δ: 7.71-7.69 (1H, m), 7.65-7.57 (3H, m), 7.55-7.45 (1H,m), 7.39- 7.33 (2H, m), 5.84 (1H, br s), 4.50-4.39 (2H, m), 3.36 (1H, brs), 2.01 (3H, s). 416

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H,m), 7.31- 7.24 (2H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.20 (2H, t, J =5.4 Hz), 3.77-3.65 (2H, m), 3.55-3.44 (3H, m), 2.33 (2H, t, J = 6.3 Hz),1.84-1.71 (4H, m). 417

¹H-NMR (CDCl₃) δ: 7.76-7.72 (1H, m), 7.65-7.60 (2H, m), 7.53 (1H, d, J =7.7 Hz), 7.48-7.43 (1H, m), 7.37- 7.33 (1H, m), 7.23-7.20 (1H, m), 3.57(1H, d, J = 13.2 Hz), 3.45 (1H, d, J = 13.2 Hz), 2.09 (3H, s).

TABLE 1-61 compound No. structural formula NMR 418

¹H-NMR (DMSO-D₆) δ: 7.87- 7.79 (2H, m), 7.65-7.61 (1H, m), 7.53-7.46(2H, m), 7.40-7.33 (2H, m), 7.30 (0.4H, s), 7.24 (0.6H, s), 4.65 (0.8H,s), 4.59 (0.6H, d, J = 15.2 Hz), 4.53 (0.6H, d, J = 15.0 Hz), 2.94(1.8H, s), 2.82 (1.2H, s), 2.09 (1.8H, s), 2.06 (1.2H, s). 419

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H,m), 7.32- 7.27 (1H, m), 7.25-7.22 (1H, m), 6.99-6.95 (1H, m), 5.99 (1H,br s), 4.11-4.04 (2H, m), 3.90-3.84 (1H, m), 3.69 (1H, s), 2.48-2.29(3H, m), 1.98-1.87 (1H, m). 420

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H,m), 7.32- 7.28 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.17-4.13(1H, m), 4.07- 4.02 (1H, m), 3.94-3.88 (1H, m), 3.17-3.07 (1H, m), 2.92(2H, s), 2.90 (1H, s), 2.60-2.48 (1H, m), 2.43- 2.33 (1H, m), 2.31-2.20(1H, m), 2.03-1.94 (1H, m). 421

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H,m), 7.32- 7.28 (1H, m), 7.24-7.22 (1H, m), 6.99-6.95 (1H, m), 4.18-4.13(1H, m), 4.07- 4.03 (1H, m), 4.01-3.95 (1H, m), 3.73 (1H, br s),3.61-3.52 (2H, m), 3.51- 3.42 (2H, m), 3.31-3.25 (1H, m), 2.66-2.56 (1H,m), 2.48-2.39 (1H, m), 2.33- 2.23 (1H, m), 2.07-1.98 (1H, m), 1.75-1.52(2H, m). 422

¹H-NMR (DMSO-D₆) δ: 9.38 (0.5H, s), 9.37 (0.5H, s), 8.96 (2H, br s),7.66-7.62 (1H, m), 7.39 (1H, d, J = 6.5 Hz), 7.32-7.22 (3H, m), 7.07(1H, dd, J = 4.6, 2.3 Hz), 6.65-6.61 (1H, m), 4.26 (1.0H, t, J = 5.2Hz), 4.18 (1.0H, t, J = 5.8 Hz), 3.73 (1.0H, t, J = 5.2 Hz), 3.66 (1.0H,t, J = 5.9 Hz), 3.08 (1.5H, s), 2.88 (1.5H, s), 2.09 (1.5H, s), 2.00(1.5H, s). 423

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.55-7.53 (1H, m), 7.50-7.48 (1H,m), 7.25- 7.20 (4H, m), 6.75 (1H, d, J = 2.6 Hz), 4.18-4.13 (2H, m),4.00 (2.1H, s), 3.99 (0.9H, s), 3.79-3.62 (3H, m), 3.16 (2.1H, s), 2.98(0.9H, s), 2.16 (0.9H, s), 2.07 (2.1H, s).

TABLE 1-62 compound No. structural formula NMR 424

¹H-NMR (DMSO-D₆) δ: 9.38 (0.4H, s), 9.37 (0.5H, s), 8.96 (2H, br s),7.66-7.62 (1H, m), 7.39 (1H, d, J = 7.2 Hz), 7.32-7.22 (3H, m), 7.07(1H, d, J = 2.3 Hz), 6.63 (1H, dd, J = 7.1, 3.4 Hz), 4.53 (0.4H, t, J =5.6 Hz), 4.48 (0.5H, t, J = 5.4 Hz), 4.28-4.19 (3H, m), 4.08 (1H, d, J =5.8 Hz), 3.72 (1.1H, t, J = 5.8 Hz), 3.66 (0.9H, t, J = 5.2 Hz), 2.99(1.7H, s), 2.94 (1.4H, s). 425

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64-7.58 (1H, m), 7.62 (1H, s),7.31-7.22 (4H, m), 7.16-7.13 (1H, m), 6.84 (1H, d, J = 2.3 Hz), 4.52(0.4H, t, J = 5.6 Hz), 4.48 (0.6H, t, J = 5.4 Hz), 4.23-4.14 (3.0H, m),4.09 (1.0H, d, J = 5.3 Hz), 3.95 (3H, s), 3.70 (1.1H, t, J = 5.7 Hz),3.64 (0.9H, t, J = 5.2 Hz), 2.99 (1.6H, s), 2.93 (1.4H, s). 426

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.66-7.53 (3H, m), 7.31-7.21 (2H, m),7.22 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.46 (1H, t,J = 5.2 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.95 (3H, s), 3.49-3.43 (2H, m),1.81-1.74 (2H, m), 1.62-1.54 (2H, m). 427

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, s),7.29-7.23 (3H, m), 7.22 (1H, s), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.4Hz), 4.07 (2H, t, J = 6.5 Hz), 3.95 (3H, s), 2.97 (3H, s), 2.83 (3H, s),2.47 (2H, t, J = 7.3 Hz), 1.99-1.92 (2H, m). 428

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.65-7.61 (1H, m),7.38- 7.35 (1H, m), 7.30-7.21 (3H, m), 7.03 (1H, d, J = 2.4 Hz), 6.61(1H, d, J = 6.8 Hz), 4.46 (1H, t, J = 5.2 Hz), 4.10 (2H, t, J = 6.5 Hz),3.47 (2H, dt, J = 6.5, 5.2 Hz), 1.82-1.75 (2H, m), 1.63-1.54 (2H, m).429

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.65-7.62 (1H, m),7.38 (1H, s), 7.31-7.22 (3H, m), 7.04 (1H, d, J = 2.3 Hz), 6.61 (1H, dd,J = 6.7, 0.9 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.97 (3H, s), 2.82 (3H, s),2.47 (2H, t, J = 7.0 Hz), 2.01-1.94 (2H, m).

TABLE 1-63 compound No. structural formula NMR 430

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 2.8 Hz), 7.81- 7.78 (1H, m),7.70-7.67 (1H, m), 7.60-7.54 (2H, m), 7.50 (1H, s), 7.48-7.44 (1H, m),4.25 (2H, t, J = 5.4 Hz), 3.59 (2H, t, J = 5.4 Hz), 3.48 (2H, t, J = 7.1Hz), 2.22 (2H, t, J = 8.1 Hz), 1.97-1.88 (2H, m). 431

¹H-NMR (CDCl₃) δ: 7.68-7.65 (1H, m), 7.59-7.54 (2H, m), 7.47-7.42 (1H,m), 7.32- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.57-4.52(2H, m), 4.24- 4.05 (3H, m), 3.84-3.77 (1H, m), 3.70-3.65 (2H, m),3.42-3.32 (1H, m), 3.31 (1.5H, s), 3.29 (1.5H, s), 3.04 (0.5H, s), 3.00(0.5H, s), 2.64-2.53 (1H, m), 2.46-2.36 (1H, m), 2.32- 2.21 (1H, m),2.08-1.98 (1H, m). 432

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H,m), 7.32- 7.28 (1H, m), 7.25-7.22 (1H, m), 6.98 (1H, dd, J = 8.2, 2.4Hz), 4.21-4.13 (1H, m), 4.10-4.03 (2H, m), 3.84-3.67 (2H, m), 3.66- 3.57(1H, m), 3.49-3.42 (1H, m), 3.28 (1H, d, J = 23.9 Hz), 3.23-3.15 (1H,m), 2.65-2.54 (1H, m), 2.47- 2.38 (1H, m), 2.37-2.26 (1H, m), 2.08-1.98(1H, m). 433

¹H-NMR (DMSO-D₆) δ: 13.07 (1H, br s), 7.97 (1H, s), 7.62-7.58 (1H, m),7.60 (1H, s), 7.30-7.23 (4H, m), 7.14-7.11 (1H, m), 6.80 (1H, d, J = 2.4Hz), 4.77 (2H, s), 3.96 (3H, s). 434

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, d, J = 2.8 Hz), 7.80 (1H, d, J = 7.4 Hz),7.72- 7.67 (2H, m), 7.61-7.59 (1H, m), 7.59-7.54 (1H, m), 7.52 (1H, s),7.49-7.44 (2H, m), 4.62 (2H, s). 435

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59 (0.2H, s), 7.56 (0.8H, s),7.51 (0.2H, s), 7.50 (0.8H, s), 7.28- 7.22 (4H, m), 6.77 (0.8H, d, J =2.6 Hz), 6.76 (0.2H, d, J = 2.6 Hz), 5.95 (1H, br s), 4.12-4.08 (2H, m),4.02 (0.6H, s), 4.02 (2.4H, s), 3.70-3.65 (2H, m), 2.02 (0.6H, s), 2.02(2.4H, s).

TABLE 1-64 compound No. structural formula NMR 436

¹H-NMR (CDCl₃) δ: 7.73-7.68 (2H, m), 7.52 (1H, s), 7.50 (1H, s),7.36-7.22 (5H, m), 4.37 (2H, t, J = 6.4 Hz), 3.71 (2H, t, J = 5.7 Hz),3.34 (1H, br s), 2.59 (1H, br s), 2.16-2.10 (2H, m). 437

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.9 Hz), 7.68- 7.64 (1H, m),7.58-7.53 (1H, m), 7.45-7.40 (1H, m), 7.44 (1H, s), 7.28 (1H, d, J = 2.4Hz), 7.22-7.20 (1H, m), 4.71 (2H, s), 4.28-4.22 (2H, m), 3.95-3.89 (2H,m), 2.30-2.22 (2H, m). 438

¹H-NMR (DMSO-D₆) δ: 8.33 (1H, d, J = 7.7 Hz), 8.19- 8.14 (1H, m),7.69-7.65 (1H, m), 7.59-7.54 (1H, m), 7.45-7.40 (1H, m), 7.44 (1H, s),7.33-7.30 (2H, m), 4.58 (2H, s), 2.67 (3H, d, J = 4.6 Hz). 439

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, d, J =0.4 Hz), 7.31-7.24 (4H, m), 7.15- 7.12 (1H, m), 6.81 (1H, d, J = 2.4Hz), 4.83-4.78 (1H, m), 4.65 (2H, s), 4.29-4.20 (1H, m), 4.01-3.87 (2H,m), 3.96 (3H, s), 3.67-3.61 (1H, m), 3.55-3.50 (2H, m), 2.74-2.65 (1H,m). 440

¹H-NMR (DMSO-D₆) δ: 7.95 (1H, s), 7.61-7.58 (1H, m), 7.59 (1H, d, J =0.7 Hz), 7.31-7.22 (3H, m), 7.23 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H,d, J = 2.4 Hz), 4.96-4.81 (2H, m), 4.53- 4.49 (1H, m), 4.37-4.30 (1H,m), 3.96 (3H, s), 3.91-3.83 (1H, m), 3.27- 3.22 (2H, m), 3.06-2.96 (1H,m), 2.63-2.53 (1H, m), 1.76-1.57 (3H, m), 1.20-1.06 (1H, m), 1.01- 0.88(1H, m). 441

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, d, J =0.7 Hz), 7.32-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H,d, J = 2.4 Hz), 4.65 (2H, s), 4.25 (2H, t, J = 8.0 Hz), 3.96 (3H, s),3.91 (2H, t, J = 7.8 Hz), 2.28-2.20 (2H, m). 442

¹H-NMR (DMSO-D₆) δ: 8.16- 8.11 (1H, m), 7.97 (1H, s), 7.63-7.59 (1H, m),7.61 (1H, d, J = 0.4 Hz), 7.31- 7.24 (3H, m), 7.25 (1H, s), 7.24-7.22(1H, m), 6.85 (1H, d, J = 2.6 Hz), 4.54 (2H, s), 3.96 (3H, s), 2.67 (3H,d, J = 4.6 Hz).

TABLE 1-65 compound No. structural formula NMR 443

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44(1H, m), 7.32-7.28 (1H, m), 7.26 (1H, br s), 7.18-7.15 (1H, m),7.11-7.06 (1H, m), 4.19 (1H, t, J = 5.1 Hz), 4.11 (1H, t, J = 5.8 Hz),3.74 (1H, t, J = 5.4 Hz), 3.66-3.61 (2H, m), 3.54-3.49 (1H, m), 2.60(1H, t, J = 7.2 Hz), 2.50-2.45 (1H, m), 2.08 (1.5H, s), 2.06 (1.5H, s).444

¹H-NMR (DMSO-D₆) δ: 7.78- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.28 (1H, m), 7.18- 7.16 (1H, m), 7.08 (1H, dd, J = 8.3,2.3 Hz), 4.16 (2H, t, J = 5.7 Hz), 3.32 (2H, s), 3.01 (2H, t, J = 5.7Hz), 2.46 (3H, s). 445

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.54 (2H, m), 7.47-7.42 (1H,m), 7.32- 7.27 (1H, m), 7.24-7.22 (1H, m), 6.99-6.94 (1H, m), 6.00 (1H,br s), 4.11-4.03 (2H, m), 3.89-3.84 (1H, m), 3.39 (0.5H, br s), 3.35(0.5H, br s), 2.46-2.28 (3H, m), 1.98-1.85 (1H, m). 446

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H,m), 7.32- 7.27 (1H, m), 7.24-7.22 (1H, m), 6.99-6.94 (1H, m), 6.00 (1H,br s), 4.10-4.03 (2H, m), 3.89-3.83 (1H, m), 3.40-3.34 (1H, m), 2.47-2.28 (3H, m), 1.97-1.85 (1H, m). 447

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H,m), 7.32- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.17-4.12(1H, m), 4.07- 4.01 (1H, m), 3.94-3.87 (1H, m), 3.16 (0.5H, s), 3.12(0.5H, s), 2.91 (1.5H, s), 2.90 (1.5H, s), 2.59- 2.48 (1H, m), 2.42-2.33(1H, m), 2.31-2.20 (1H, m), 2.03-1.93 (1H, m). 448

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H,m), 7.32- 7.28 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.18-4.13(1H, m), 4.07- 4.02 (1H, m), 3.94-3.88 (1H, m), 3.06 (0.5H, s), 3.04(0.5H, s), 2.92 (1.5H, s), 2.91 (1.5H, s), 2.60- 2.49 (1H, m), 2.43-2.33(1H, m), 2.31-2.21 (1H, m), 2.03-1.94 (1H, m).

TABLE 1-66 compound No. structural formula NMR 449

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 7.98 (1H, s), 7.61-7.58 (1H, m),7.61 (1H, s), 7.31-7.22 (3H, m), 7.22 (1H, s), 7.15-7.12 (1H, m), 6.82(1H, d, J = 2.6 Hz), 4.06 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 2.40 (2H,t, J = 7.2 Hz), 2.00-1.92 (2H, m). 450

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44(1H, m), 7.32-7.28 (1H, m), 7.25- 7.24 (1H, m), 7.16-7.14 (1H, m),7.10-7.06 (1H, m), 4.86 (1H, t, J = 5.3 Hz), 4.20-4.07 (2H, m), 3.87-3.79 (1H, m), 3.76-3.68 (1H, m), 3.65-3.59 (1H, m), 3.50-3.36 (2H, m),2.34- 2.23 (1H, m), 2.20-2.11 (1H, m), 2.03-1.93 (1H, m), 1.84-1.74 (1H,m). 451 (optically active form)

enantiomer of compound No. 452 ¹H-NMR (CDCl₃) δ: 8.39 (1H, d, J = 7.9Hz), 7.70-7.67 (1H, m), 7.53-7.48 (1H, m), 7.39-7.35 (1H, m), 7.26- 7.24(1H, m), 7.16 (1H, d, J = 2.3 Hz), 4.68 (2H, s), 3.83 (3H, s), 2.77 (1H,s). 452 (optically active form)

enantiomer of compound No. 451 ¹H-NMR (CDCl₃) δ: 8.41-8.38 (1H, m),7.70-7.67 (1H, m), 7.53-7.49 (1H, m), 7.39- 7.35 (1H, m), 7.27-7.25 (1H,m), 7.17 (1H, d, J = 2.3 Hz), 4.69 (2H, s), 3.84 (3H, s), 2.73 (1H, s).453

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64-7.58 (1H, m), 7.61 (1H, s),7.29-7.21 (3H, m), 7.22 (1H, s), 7.16- 7.12 (1H, m), 6.82 (1H, d, J =2.6 Hz), 4.57 (1H, t, J = 5.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 3.95 (3H,s), 3.57 (2H, dt, J = 6.6, 5.3 Hz), 1.93-1.94 (2H, m). 454

¹H-NMR (DMSO-D₆) δ: 12.41 (1H, br s), 7.99 (1H, s), 7.63-7.57 (1H, m),7.62 (1H, s), 7.31-7.23 (3H, m), 7.24 (1H, s), 7.15-7.12 (1H, m), 6.82(1H, d, J = 2.3 Hz), 4.25 (2H, t, J = 6.0 Hz), 3.96 (3H, s), 2.73 (2H,t, J = 6.0 Hz). 455

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.56 (1H, m), 7.61 (1H, s),7.29-7.22 (3H, m), 7.14 (1H, s), 7.14- 7.11 (1H, m), 6.80 (1H, d, J =2.6 Hz), 4.26 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 3.01 (3H, s), 2.86-2.79(2H, m), 2.85 (3H, s).

TABLE 1-67 compound No. structural formula NMR 456

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, d, J =0.7 Hz), 7.31-7.22 (4H, m), 7.16-7.14 (1H, m), 6.82 (1H, d, J = 2.6 Hz),4.90 (1H, t, J = 5.6 Hz), 4.06 (2H, t, J = 4.9 Hz), 3.95 (3H, s), 3.73(2H, dt, J = 5.6, 4.9 Hz). 457

¹H-NMR (DMSO-D₆) δ: 7.95-7.94 (1H, m), 7.61-7.57 (1H, m), 7.59 (1H, d, J= 0.7 Hz), 7.30-7.21 (3H, m), 7.22 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H,d, J = 2.4 Hz), 4.89 (2H, br s), 3.95 (3H, s), 3.00 (3H, s), 2.85 (3H,s). 458

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz),7.61-7.57 (1H, m), 7.33-7.22 (3H, m), 7.23 (1H, s), 7.15-7.13 (1H, m),6.84 (1H, d, J = 2.3 Hz), 4.97 (1H, t, J = 5.3 Hz), 4.25 (2H, t, J = 5.6Hz), 3.85-3.80 (2H, m), 3.84 (3H, s). 459

¹H-NMR (DMSO-D₆) δ: 7.79-7.74 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H,m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19- 7.16 (1H, m), 7.10 (1H, dd, J= 8.4, 2.4 Hz), 4.30-4.24 (2H, m), 4.19 (2H, t, J = 5.3 Hz), 3.70-3.65(2H, m), 3.57 (2H, t, J = 5.3 Hz). 460

¹H-NMR (CDCl₃) δ: 7.71-7.68 (1H, m), 7.67-7.65 (1H, m), 7.62 (1H, d, J =0.7 Hz), 7.60 (1H, s), 7.35-7.26 (4H, m), 4.37-4.34 (2H, m), 4.13-4.08(2H, m), 3.03 (1H, s), 2.89 (1H, t, J = 5.9 Hz). 461

¹H-NMR (CDCl₃) δ: 7.78-7.74 (2H, m), 7.47-7.44 (1H, m), 7.41-7.33 (4H,m), 7.29-7.24 (1H, m), 4.96 (1H, br s), 4.38-4.24 (4H, m), 4.18-4.10(2H, m), 4.08-4.03 (2H, m), 3.47 (1H, br s), 2.37-2.28 (2H, m). 462

¹H-NMR (DMSO-D₆) δ: 12.85 (1H, br s), 7.76-7.72 (2H, m), 7.60-7.57 (1H,m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.23 (1H, br s), 7.18-7.15(1H, m), 7.03-6.99 (1H, m), 4.96 (1.2H, s), 4.80 (0.8H, s), 4.19 (0.8H,s), 4.02 (1.2H, s), 3.07 (1.8H, s), 2.86 (1.2H, s).

TABLE 1-68 compound No. structural formula NMR 463

¹H-NMR (CDCl₃) δ: 7.68-7.63 (1H, m), 7.51-7.46 (1H, m), 7.47 (1H, s),7.29-7.19 (4H, m), 6.77 (1H, d, J = 2.4 Hz), 3.99 (3H, s), 3.87 (3H, s),3.24 (1H, br s). 464

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, s), 7.72 (1H, br s), 7.63-7.59 (1H, m),7.62 (1H, s), 7.31-7.23 (3H, m), 7.28 (1H, s), 7.17-7.13 (1H, m), 6.83(1H, d, J = 2.4 Hz), 4.23-4.08 (2H, m), 3.96 (3H, s), 3.78-3.67 (1H, m),3.55-3.45 (1H, m), 2.53-2.42 (3H, m), 2.20- 2.08 (1H, m). 465

¹H-NMR (CDCl₃) δ: 7.73-7.68 (2H, m), 7.51-7.50 (1H, m), 7.36-7.14 (6H,m), 4.57-4.50 (1H, m), 3.70 (1H, br s), 1.55 (3H, s), 1.54 (3H, s). 466

¹H-NMR (CDCl₃) δ: 7.70-7.65 (2H, m), 7.57 (1H, s), 7.50 (1H, s),7.42-7.25 (8H, m), 7.22-7.14 (2H, m), 5.39 (2H, s), 2.99 (1H, br s). 467(optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.64-7.59 (2H, m), 7.60 (1H, s), 7.41(1H, br s), 7.30-7.25 (3H, m), 7.24 (1H, s), 7.23-7.20 (1H, m), 6.84(1H, d, J = 2.4 Hz), 4.50 (2H, s), 3.96 (3H, s). 468

¹H-NMR (DMSO-D₆) δ: 7.78- 7.85 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44(1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19-7.16 (1H, m), 7.09 (1H,dd, J = 8.4, 2.4 Hz), 4.19 (2H, t, J = 5.4 Hz), 3.39-3.30 (4H, m), 3.23-3.18 (2H, m), 2.29-2.21 (2H, m). 469

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43(1H, m), 7.32-7.27 (1H, m), 7.24 (1H, s), 7.18-7.15 (1H, m), 7.09 (1H,dd, J = 8.4, 2.4 Hz), 6.38 (1H, s), 4.15- 4.09 (2H, m), 3.50-3.41 (4H,m), 3.26-3.20 (2H, m).

TABLE 1-69 compound No. structural formula NMR 470

¹H-NMR (DMSO-D₆) δ: 7.78- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43(1H, m), 7.33-7.27 (1H, m), 7.25 (1H, s), 7.19-7.17 (1H, m), 7.10 (1H,dd, J = 8.3, 2.3 Hz), 4.21-4.14 (4H, m), 3.66- 3.56 (2H, m), 3.45 (2H,t, J = 6.2 Hz), 1.97-1.90 (2H, m). 471

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.59-(1H, s), 7.50 (1H, s),7.28-7.21 (4H, m), 6.77 (1H, d, J = 2.3 Hz), 4.19 (2H, t, J = 5.4 Hz),4.01 (3H, s), 3.81-3.68 (2H, m), 3.26 (3H, br s), 3.14 (1H, s), 1.28(9H, s). 472

¹H-NMR (DMSO-D₆) δ: 8.54 (1H, d, J = 7.9 Hz), 8.24 (1H, d, J = 1.5 Hz),8.18- 8.16 (1H, m), 7.79-7.76 (1H, m), 7.70-7.65 (1H, m), 7.64 (1H, s),7.62-7.58 (1H, m), 3.92 (3H, s). 473 (optically active form)

¹H-NMR (CDCl₃) δ: 8.58 (1H, d, J = 7.7 Hz), 8.34 (1H, d, J = 1.3 Hz),8.30-8.29 (1H, m), 7.78-7.75 (1H, m), 7.60-7.56 (1H, m), 7.52-7.48 (1H,m), 3.95 (3H, s), 2.84 (1H, s). 474 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, s),7.32-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4Hz), 4.82- 4.79 (1H, m), 4.65 (2H, s), 4.28-4.22 (1H, m), 4.01- 3.87(2H, m), 3.96 (3H, s), 3.64 (1H, dd, J = 9.5, 5.3 Hz), 3.54-3.49 (2H,m), 2.74-2.66 (1H, m). 475 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, s),7.30-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4Hz), 5.76 (1H, d, J = 6.0 Hz), 4.69 (1H, d, J = 14.8 Hz), 4.65 (1H, d, J= 14.8 Hz), 4.54- 4.39 (2H, m), 4.15-4.08 (1H, m), 4.00-3.94 (1H, m),3.96 (3H, s), 3.67-3.62 (1H, m). 476

¹H-NMR (CDCl₃) δ: 7.80-7.76 (1H, m), 7.72-7.70 (1H, m), 7.38-7.32 (3H,m), 7.27- 7.22 (1H, m), 7.13 (1H, d, J = 1.6 Hz), 7.06 (1H, s), 5.42(1H, br s), 4.22-4.18 (2H, m), 4.02-3.98 (2H, m), 3.96 (1H, br s),3.64-3.58 (2H, m), 3.47-3.40 (2H, m), 2.02-1.85 (4H, m).

TABLE 1-70 compound No. structural formula NMR 477 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.62-7.59 (2H, m), 7.41(1H, br s), 7.34-7.30 (1H, m), 7.29-7.23 (3H, m), 7.22-7.20 (1H, m),6.86 (1H, d, J = 2.2 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.51 (2H, s), 4.26(2H, t, J = 5.6 Hz), 3.83 (2H, dt, J = 5.6, 5.2 Hz). 478

¹H-NMR (DMSO-D₆) δ: 12.17 (1H, s), 8.14 (1H, d, J = 7.7 Hz), 7.67-7.64(1H, m), 7.56-7.51 (1H, m), 7.43- 7.38 (1H, m), 7.42 (1H, s), 7.17-7.15(2H, m), 4.09 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01- 1.92(2H, m). 479 (optically (active form)

¹H-NMR (DMSO-D₆) δ: 8.14 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = 7.7 Hz),7.56- 7.52 (1H, m), 7.43-7.38 (1H, m), 7.42 (1H, br s), 7.16 (2H, s),4.09 (2H, t, J = 6.5 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99-1.93 (2H, m).480

¹H-NMR (CDCl₃) δ: 8.23-8.20 (1H, m), 7.70-7.67 (1H, m), 7.51-7.47 (1H,m), 7.38- 7.33 (1H, m), 7.21-7.19 (1H, m), 6.97 (1H, d, J = 2.2 Hz),4.68 (2H, s), 3.83 (3H, s), 2.78 (1H, s). 481 (optically active form)

¹H-NMR (CDCl₃) δ: 8.23-8.20 (1H, m), 7.70-7.67 (1H, m), 7.52-7.47 (1H,m), 7.38- 7.33 (1H, m), 7.21-7.20 (1H, m), 6.97 (1H, d, J = 2.2 Hz),4.69 (2H, s), 3.84 (3H, s), 2.75 (1H, s). 482

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.56 (1H, m), 7.34-7.29 (1H, m), 7.28-7.19 (3H, m), 7.15-7.12 (1H, m), 6.83 (1H, d, J = 2.4Hz), 4.25 (2H, t, J = 5.6 Hz), 4.06 (2H, t, J = 6.4 Hz), 3.82 (2H, t, J= 5.6 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00-1.93 (2H, m). 483

¹H-NMR (DMSO-D₆) δ: 13.20 (1H, br s), 8.00 (1H, d, J = 0.7 Hz),7.66-7.61 (2H, m), 7.63 (1H, d, J = 0.7 Hz), 7.42-7.37 (2H, m),7.36-7.21 (4H, m), 5.07 (2H, s).

TABLE 1-71 compound No. structural formula NMR 484

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64 (1H, s), 7.61-7.58 (1H, m), 7.35-7.32 (1H, m), 7.28-7.23 (2H, m), 7.24 (1H, s), 7.14-7.12 (1H, m), 6.85(1H, d, J = 2.3 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.7 Hz),4.16 (2H, t, J = 5.2 Hz), 3.85- 3.79 (2H, m), 3.57 (2H, t, J = 5.4 Hz),3.47 (2H, t, J = 7.3 Hz), 2.22 (2H, t, J = 8.1 Hz), 1.96-1.88 (2H, m).485

¹H-NMR (DMSO-D₆) δ: 12.44 (1H, br s), 7.98 (1H, s), 7.66-7.60 (2H, m),7.61 (1H, s), 7.41-7.26 (5H, m), 7.21 (1H, s), 4.43 (2H, t, J = 6.6 Hz),2.90 (2H, t, J = 6.5 Hz). 486

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.61 (1H, s), 7.59 (1H, s),7.36-7.22 (5H, m), 5.76 (1H, br s), 5.33 (1H, br s), 4.55 (2H, t, J =6.3 Hz), 2.95 (1H, br s), 2.91 (2H, t, J = 6.1 Hz). 487

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.54 (1H, s), 7.52 (1H, s),7.35-7.21 (5H, m), 5.69 (1H, br s), 4.51 (2H, t, J = 6.3 Hz), 3.26 (1H,br s), 2.82 (2H, t, J = 6.3 Hz), 2.77 (3H, d, J = 4.6 Hz). 488

¹H-NMR (CDCl₃) δ: 7.72-7.66 (2H, m), 7.59 (1H, s), 7.55 (1H, s),7.34-7.23 (5H, m), 4.53 (2H, t, J = 6.5 Hz), 3.22 (1H, br s), 3.01 (3H,s), 3.00-2.96 (2H, m), 2.95 (3H, s). 489

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.58 (1H, s), 7.50 (1H, s),7.25-7.20 (4H, m), 6.77 (1H, d, J = 1.6 Hz), 4.29-4.17 (2H, m), 4.01(3H, s), 3.80-3.72 (2H, m), 3.68 (1H, t, J = 7.2 Hz), 3.53-3.40 (2H, m),3.42 (1H, br s), 3.24 (3H, br s), 1.27 (3H, s), 1.24 (3H, s). 490

¹H-NMR (DMSO-D₆) δ: 7.79- 7.74 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44(1H, m), 7.33-7.28 (1H, m), 7.24 (1H, s), 7.19-7.16 (1H, m), 7.10 (1H,dd, J = 8.4, 2.4 Hz), 4.20 (2H, t, J = 5.6 Hz), 4.05 (2H, s), 3.82 (2H,t, J = 5.1 Hz), 3.74- 3.69 (2H, m), 3.54-3.50 (2H, m).

TABLE 1-72 compound No. structural formula NMR 491

¹H-NMR (DMSO-D₆) δ: 13.15 (1H, br s), 8.01 (1H, br s), 7.67 (1H, br s),7.61- 7.58 (1H, m), 7.28-7.24 (2H, m), 7.22 (1H, s), 7.20-7.17 (1H, m),7.15- 7.13 (1H, m), 6.86 (1H, d, J = 2.4 Hz), 4.16 (2H, t, J = 5.4 Hz),3.57 (2H, t, J = 5.5 Hz), 3.47 (2H, t, J = 7.2 Hz), 2.22 (2H, t, J = 8.0Hz), 1.96-1.88 (2H, m). 492

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, s), 7.64-7.58 (1H, m), 7.60 (1H, s),7.44-7.41 (1H, m), 7.36-7.25 (3H, m), 7.14 (1H, s), 7.12 (1H, d, J = 7.0Hz), 4.95 (1H, t, J = 5.1 Hz), 4.25 (2H, t, J = 5.7 Hz), 3.83 (2H, dt, J= 5.7, 5.1 Hz), 2.39 (3H, s). 493

¹H-NMR (CDCl₃) δ: 7.77 (1H, s), 7.73-7.69 (2H, m), 7.64 (1H, s),7.38-7.25 (5H, m), 6.42 (1H, br s), 5.52 (1H, br s), 4.92 (2H, s), 2.79(1H, br s). 494

¹H-NMR (CDCl₃) δ: 7.76 (1H, s), 7.73-7.70 (2H, m), 7.61 (1H, s),7.39-7.25 (5H, m), 6.42 (1H, br s), 4.90 (2H, s), 2.89 (3H, d, J = 4.9Hz), 2.84 (1H, br s). 495

¹H-NMR (CDCl₃) δ: 7.70-7.66 (2H, m), 7.63 (1H, s), 7.61 (1H, s),7.45-7.42 (1H, m), 7.35-7.27 (4H, m), 5.09 (1H, d, J = 16.0 Hz), 5.03(1H, d, J = 16.0 Hz), 3.14 (3H, s), 3.03 (3H, s), 2.99 (1H, br s). 496

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.62 (1H, s), 7.61-7.57 (1H, m), 7.33-7.29 (1H, m), 7.28-7.23 (3H, m), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.4Hz), 4.97 (1H, t, J = 5.2 Hz), 4.66 (2H, s), 4.25 (4H, t, J = 5.7 Hz),3.91 (2H, t, J = 7.7 Hz), 3.82 (2H, dt, J = 5.7, 5.2 Hz), 2.28-2.21 (2H,m). 497

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.58 (1H, m), 7.33-7.29 (1H, m), 7.28-7.24 (3H, m), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.6Hz), 5.77 (1H, d, J = 5.5 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.72-4.64 (2H,m), 4.52- 4.40 (2H, m), 4.25 (2H, t, J = 5.5 Hz), 4.14-4.08 (1H, m),4.00-3.94 (1H, m), 3.82 (2H, dt, J = 5.5, 5.2 Hz), 3.67-3.61 (1H, m).

TABLE 1-73 compound No. structural formula NMR 498

¹H-NMR (DMSO-D₆) δ: 7.83 (2H, br s), 7.61-7.57 (1H, m), 7.29-7.12 (5H,m), 6.84 (1H, d, J = 2.4 Hz), 4.06 (2H, t, J = 6.4 Hz), 2.40 (2H, t, J =7.3 Hz), 2.00- 1.92 (2H, m). 499

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.52 (1H, s), 7.47 (1H, s),7.25-7.20 (4H, m), 6.78-6.76 (1H, m), 4.25- 4.11 (2H, m), 4.06-3.89 (2H,m), 3.98 (3H, s), 3.68-3.52 (2H, m), 3.10 (3H, s), 2.11 (3H, s). 500

¹H-NMR (CDCl₃) δ: 7.70-7.65 (1H, m), 7.52 (1H, s), 7.48 (1H, s),7.25-7.21 (4H, m), 6.79-6.76 (1H, m), 4.27 (1H, dd, J = 20.9, 4.2 Hz),4.21-4.12 (1H, m), 4.06- 3.89 (2H, m), 3.99 (3H, s), 3.69-3.53 (2H, m),3.11 (3H, s), 2.12 (3H, s). 501

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.56 (1H, s), 7.50 (1H, s),7.25-7.22 (4H, m), 6.78-6.75 (1H, m), 4.43 (1H, br s), 4.26-4.21 (2H,m), 4.02-3.99 (3H, m), 3.87-3.77 (2H, m), 3.37- 3.21 (3H, m), 1.58-1.56(6H, m). 502

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.87-7.84 (1H, m), 7.72 (1H, br s),7.63- 7.59 (1H, m), 7.46-7.40 (1H, m), 7.35-7.29 (2H, m), 7.23-7.21 (1H,m), 7.06- 7.04 (1H, m), 4.22-4.16 (2H, m), 3.61-3.56 (2H, m), 3.51-3.45(2H, m), 2.27- 2.20 (2H, m), 1.98-1.89 (2H, m). 503

¹H-NMR (DMSO-D₆) δ: 7.82 (2H, br s), 7.63 (1H, br s), 7.61-7.58 (1H, m),7.41 (1H, br s), 7.28-7.16 (5H, m), 6.86 (1H, d, J = 2.4 Hz), 4.51 (2H,s). 504 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.26 (1H, br s), 7.99-7.96 (1H, m), 7.62-7.57 (2H,m), 7.29-7.20 (4H, m), 7.15- 7.12 (1H, m), 6.83-6.80 (1H, m), 4.05 (2H,t, J = 6.1 Hz), 3.95 (3H, s), 2.39 (2H, t, J = 7.0 Hz), 2.00- 1.92 (2H,m).

TABLE 1-74 compound No. structural formula NMR 505

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, d, J = 1.2 Hz), 7.67 (1H, d, J = 1.2 Hz),7.65- 7.61 (1H, m), 7.41-7.36 (3H, m), 7.35-7.27 (2H, m), 7.18-7.14 (1H,m), 4.99- 4.95 (1H, m), 4.24 (2H, t, J = 4.9 Hz), 3.84-3.78 (2H, m). 506

¹H-NMR (CDCl₃) δ: 7.76-7.73 (1H, m), 7.72-7.67 (2H, m), 7.66-7.63 (1H,m), 7.36- 7.22 (4H, m), 6.38 (1H, s), 5.57 (1H, s), 4.93-4.88 (2H, m),2.98 (1H, br s). 507

¹H-NMR (CDCl₃) δ: 7.74-7.73 (1H, m), 7.71-7.67 (1H, m), 7.61-7.61 (1H,m), 7.54- 7.51 (1H, m), 7.32-7.19 (3H, m), 7.11-7.09 (1H, m), 6.41 (1H,br s), 5.58 (1H, br s), 4.90-4.88 (2H, m), 2.97 (1H, br s), 2.45-2.42(3H, m). 508

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.9 Hz),7.60- 7.55 (1H, m), 7.57 (1H, br s), 7.42-7.37 (1H, m), 7.32 (1H, br s),7.27-7.22 (2H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.84 (1H, d, J = 2.4Hz), 4.87 (2H, s), 4.10 (2H, t, J = 6.8 Hz), 1.97- 1.91 (3H, m),1.72-1.53 (14H, m). 509

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.4 Hz), 7.64 (1H, d, J = 0.7 Hz),7.60- 7.57 (1H, m), 7.32-7.22 (3H, m), 7.20 (1H, s), 7.13- 7.11 (1H, m),6.83 (1H, d, J = 2.4 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.6Hz), 4.10 (2H, t, J = 6.8 Hz), 3.84-3.80 (2H, m), 1.97-1.91 (3H, m),1.71-1.52 (14H, m). 510

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.95 (2H, br s), 7.65-7.62 (1H, m),7.37 (1H, br s), 7.31-7.21 (3H, m), 7.04-7.04 (1H, m), 6.61 (1H, dd, J =6.7, 1.0 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.40 (2H, t, J = 7.3 Hz),2.01-1.95 (2H, m). 511

¹H-NMR (DMSO-D₆) δ: 8.20- 8.16 (1H, m), 7.96 (1H, d, J = 0.7 Hz),7.66-7.60 (2H, m), 7.62 (1H, d, J = 0.9 Hz), 7.46-7.43 (1H, m),7.42-7.27 (4H, m), 7.22 (1H, s), 4.87 (2H, s), 3.20-3.13 (2H, m), 1.08(3H, t, J = 7.2 Hz).

TABLE 1-75 compound No. structural formula NMR 512

¹H-NMR (DMSO-D₆) δ: 8.13- 8.08 (1H, m), 7.95 (1H, d, J = 2.6 Hz),7.64-7.59 (1H, m), 7.61 (1H, d, J = 2.6 Hz), 7.45-7.40 (2H, m),7.34-7.25 (2H, m), 7.19- 7.12 (2H, m), 4.90-4.86 (2H, m), 2.70-2.67 (3H,m), 2.41-2.37 (3H, m). 513

¹H-NMR (DMSO-D₆) δ: 8.13- 8.07 (1H, m), 8.06 (1H, d, J = 2.6 Hz), 7.70(1H, d, J = 2.6 Hz), 7.68-7.64 (1H, m), 7.61-7.58 (1H, m), 7.51-7.47(1H, m), 7.45- 7.43 (1H, m), 7.42-7.31 (3H, m), 4.91-4.87 (2H, m),2.70-2.66 (3H, m). 514

¹H-NMR (DMSO-D₆) δ: 8.12- 8.08 (1H, m), 7.95 (1H, d, J = 0.7 Hz),7.66-7.60 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.46-7.26 (5H, m), 7.22(1H, s), 4.85 (2H, s), 3.93-3.85 (1H, m), 1.11 (6H, d, J = 6.6 Hz). 515

¹H-NMR (DMSO-D₆) δ: 8.13- 8.08 (1H, m), 8.04 (1H, d, J = 0.9 Hz), 7.68(1H, d, J = 0.9 Hz), 7.67-7.63 (1H, m), 7.49-7.45 (1H, m), 7.43-7.39(2H, m), 7.37- 7.29 (2H, m), 7.18 (1H, dd, J = 9.9, 2.4 Hz), 4.89 (2H,s), 2.68 (3H, d, J = 4.4 Hz). 516

¹H-NMR (DMSO-D₆) δ: 13.18 (1H, br s), 8.40 (1H, s), 8.23 (1H, d, J = 7.9Hz), 8.10 (1H, s), 7.84 (1H, d, J = 1.4 Hz), 7.80-7.78 (1H, m),7.72-7.69 (1H, m), 7.61-7.56 (1H, m), 7.49- 7.45 (2H, m), 5.00 (2H, s).517

¹H-NMR (DMSO-D₆) δ: 12.42 (1H, s), 8.41 (1H, s), 8.22 (1H, d, J = 7.9Hz), 8.06 (1H, d, J = 0.7 Hz), 7.82 (1H, d, J = 1.6 Hz), 7.80- 7.78 (1H,m), 7.72-7.69 (1H, m), 7.60-7.55 (1H, m), 7.49-7.44 (1H, m), 7.45 (1H,s), 4.35 (2H, t, J = 6.7 Hz), 2.86 (2H, t, J = 6.8 Hz). 518

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, s), 8.15 (1H, br s), 7.98 (1H, d, J = 0.8Hz), 7.91 (1H, d, J = 7.5 Hz), 7.84-7.81 (1H, m), 7.75 (1H, br s), 7.69(1H, d, J = 1.9 Hz), 7.67-7.63 (1H, m), 7.49-7.43 (1H, m), 7.40-7.34(1H, m), 7.31 (1H, s), 3.89 (3H, s).

TABLE 1-76 compound No. structural formula NMR 519

¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J = 7.9 Hz), 7.72-7.68 (1H, m), 7.53-7.47(1H, m), 7.44-7.42 (1H, m), 7.40- 7.35 (1H, m), 7.26-7.25 (1H, m), 2.76(1H, s), 2.41 (3H, s). 520 (optically active form)

¹H-NMR (CDCl₃) δ: 8.28 (1H, d, J = 7.7 Hz), 7.72-7.68 (1H, m), 7.53-7.48(1H, m), 7.44-7.42 (1H, m), 7.41- 7.36 (1H, m), 7.27-7.25 (1H, m), 2.69(1H, s), 2.41 (3H, s). 521

¹H-NMR (DMSO-D₆) δ: 8.34 (1H, s), 8.22 (1H, d, J = 7.7 Hz), 8.05 (1H, d,J = 0.7 Hz), 7.81 (1H, d, J = 1.5 Hz), 7.79-7.76 (1H, m), 7.72- 7.68(1H, m), 7.60-7.55 (1H, m), 7.49-7.43 (1H, m), 7.44 (1H, s), 7.42 (1H,br s), 6.91 (1H, br s), 4.33 (2H, t, J = 6.8 Hz), 2.67 (2H, t, J = 6.9Hz). 522

¹H-NMR (CDCl₃) δ: 7.71-7.66 (2H, m), 7.64 (1H, d, J = 0.7 Hz), 7.51 (1H,d, J = 0.7 Hz), 7.36-7.22 (5H, m), 3.06 (1H, br s), 2.30-2.25 (3H, m),2.24-2.22 (6H, m), 1.82-1.78 (6H, m). 523

¹H-NMR (CDCl₃) δ: 7.72-7.66 (2H, m), 7.64 (1H, d, J = 0.7 Hz), 7.53-7.50(1H, m), 7.36-7.22 (5H, m), 3.06-3.00 (1H, br m), 1.67 (9H, s). 524

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.51-7.49 (1H, m), 7.47 (1H, s),7.36-7.19 (5H, m), 3.99 (2H, s), 3.10 (1H, s), 1.04 (9H, br s). 525

¹H-NMR (CDCl₃) δ: 8.30-8.26 (1H, m), 7.74-7.70 (1H, m), 7.56-7.50 (1H,m), 7.44- 7.35 (2H, m), 7.23-7.18 (1H, m), 2.82-2.81 (1H, m).

TABLE 1-77 compound No. structural formula NMR 526 (optically activeform)

¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J = 7.7 Hz), 7.73-7.70 (1H, m), 7.55-7.50(1H, m), 7.43-7.35 (2H, m), 7.30 (1H, dd, J = 8.6, 2.2 Hz), 2.76 (1H,s). 527

¹H-NMR (CDCl₃) δ: 7.74-7.69 (2H, m), 7.51 (1H, s), 7.46 (1H, s),7.36-7.28 (2H, m), 7.24-7.21 (3H, m), 6.11 (1H, br s), 4.30 (2H, dd, J =6.2, 4.9 Hz), 3.77- 3.72 (2H, m), 3.54 (1H, br s), 1.98 (3H, s). 528

¹H-NMR (DMSO-D₆) δ: 8.42 (1H, d, J = 0.7 Hz), 8.14 (1H, br s), 7.98 (1H,d, J = 0.7 Hz), 7.93-7.90 (1H, m), 7.87-7.85 (1H, m), 7.75 (1H, br s),7.72 (1H, d, J = 1.6 Hz), 7.67-7.63 (1H, m), 7.49-7.44 (1H, m),7.40-7.35 (1H, m), 7.31 (1H, s), 4.58-4.48 (1H, m), 1.47 (3H, s), 1.46(3H, s). 529 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.9 Hz), 7.63- 7.58 (1H, m), 7.60(1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.36-7.33 (1H, m), 7.32- 7.25(2H, m), 7.16 (1H, s), 7.12 (1H, dd, J = 1.7, 0.8 Hz), 4.97 (1H, t, J =5.3 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.3, 5.6 Hz), 2.38(3H, s). 530

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, s), 8.15 (1H, br s), 7.98 (1H, s), 7.91(1H, d, J = 7.7 Hz), 7.85-7.83 (1H, m), 7.75 (1H, br s), 7.70 (1H, d, J= 1.6 Hz), 7.66- 7.64 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m),7.31 (1H, s), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.2 Hz). 531(optically active form)

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.7 Hz),7.66- 7.63 (1H, m), 7.42-7.38 (3H, m), 7.36-7.29 (2H, m), 7.18 (1H, dd,J = 10.0, 2.6 Hz), 4.99 (1H, t, J = 5.3 Hz), 4.26 (2H, t, J = 5.6 Hz),3.82 (2H, dt, J = 5.6, 5.3 Hz). 532 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64-7.59 (1H, m), 7.60(1H, d, J = 0.7 Hz), 7.57 (1H, br s), 7.46- 7.43 (2H, m), 7.32-7.24 (2H,m), 7.32 (1H, br s), 7.17 (1H, s), 7.14 (1H, dd, J = 1.5, 0.9 Hz), 4.88(2H, s), 2.40 (3H, s).

TABLE 1-78 compound No. structural formula NMR 533 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 8.12- 8.06 (1H, m), 7.95 (1H, d, J = 0.7 Hz),7.64-7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.39 (2H, m),7.33-7.25 (2H, m), 7.17 (1H, s), 7.13 (1H, d, J = 0.7 Hz), 4.88 (2H, s),2.68 (3H, d, J = 4.6 Hz), 2.39 (3H, s). 534 (optically active form)

¹H-NMR (CDCl₃) δ: 7.74 (1H, s), 7.72-7.68 (1H, m), 7.62 (1H, s),7.46-7.40 (1H, m), 7.34-7.19 (3H, m), 7.01 (1H, dd, J = 9.4, 2.6 Hz),6.40 (1H, s), 4.88 (2H, s), 3.06 (1H, s), 2.88 (3H, br s). 535

¹H-NMR (CDCl₃) δ: 7.75-7.69 (2H, m), 7.62 (0.2H, s), 7.56 (0.8H, s),7.45 (0.2H, s), 7.41 (0.8H, s), 7.36- 7.20 (5H, m), 4.39-4.32 (2H, m),3.87-3.79 (2H, m), 2.96 (0.8H, s), 2.82 (2.2H, s), 2.04 (2.2H, s), 1.83(0.8H, s). 536

¹H-NMR (DMSO-D₆) δ: 8.33- 8.31 (1H, m), 8.16 (1H, br s), 8.01-7.99 (1H,m), 7.94-7.90 (1H, m), 7.86- 7.83 (1H, m), 7.76 (1H, br s), 7.72-7.69(1H, m), 7.68-7.63 (1H, m), 7.50- 7.44 (1H, m), 7.41-7.35 (1H, m), 7.33(1H, br s), 4.95 (1H, br s), 4.21-4.16 (2H, m), 3.82-3.76 (2H, m). 537(optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.67 (1H, m), 7.54 (1H, s), 7.53 (1H, s),7.42-7.38 (1H, m), 7.30-7.19 (3H, m), 6.98 (1H, dd, J = 9.4, 2.5 Hz),4.30 (2H, t, J = 6.7 Hz), 2.42 (2H, t, J = 7.1 Hz), 2.27-2.20 (2H, m).538 (optically active form)

¹H-NMR (CDCl₃) δ: 7.69-7.63 (1H, m), 7.58-7.54 (2H, m), 7.52-7.49 (1H,m), 7.25- 7.14 (3H, m), 7.07-7.05 (1H, m), 4.48 (2H, t, J = 6.2 Hz),3.00 (2H, t, J = 6.2 Hz), 2.41 (3H, s). 539 (optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.65 (1H, m), 7.55 (1H, s), 7.52- 7.49 (2H, m),7.29-7.20 (3H, m), 7.09-7.07 (1H, m), 4.31 (2H, t, J = 6.6 Hz),2.45-2.39 (2H, m), 2.42 (3H, s), 2.28-2.20 (2H, m).

TABLE 1-79 compound No. structural formula NMR 540 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.62 (1H, d, J = 0.7 Hz), 7.61-7.58(1H, m), 7.29-7.23 (3H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.83 (1H,d, J = 2.4 Hz), 4.35 (1H, s), 4.09 (2H, t, J = 7.2 Hz), 3.96 (3H, s),2.13-2.07 (2H, m), 1.61 (2H, t, J = 6.8 Hz), 1.57- 1.43 (12H, m). 541(optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.9 Hz), 7.64 (1H, d, J = 0.9 Hz),7.60- 7.56 (2H, m), 7.41-7.38 (1H, m), 7.32 (1H, br s), 7.26-7.22 (2H,m), 7.21 (1H, s), 7.13-7.12 (1H, m), 6.84 (1H, d, J = 2.4 Hz), 4.87 (2H,s), 4.09 (2H, t, J = 6.9 Hz), 3.57 (1H, s), 2.12-2.07 (2H, m), 1.61 (2H,t, J = 7.2 Hz), 1.56- 1.42 (12H, m). 542 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz),7.61- 7.56 (1H, m), 7.33-7.28 (1H, m), 7.28-7.22 (2H, m), 7.21 (1H, s),7.13-7.11 (1H, m), 6.83 (1H, d, J = 2.6 Hz), 4.97 (1H, t, J = 5.3 Hz),4.36 (1H, s), 4.25 (2H, t, J = 5.7 Hz), 4.09 (2H, t, J = 7.1 Hz), 3.82(2H, dt, J = 5.3, 5.7 Hz), 2.12-2.07 (2H, m), 1.60 (2H, t, J = 7.0 Hz),1.56- 1.42 (13H, m). 543 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.9 Hz),7.66- 7.62 (1H, m), 7.43-7.38 (1H, m), 7.36-7.28 (4H, m), 7.17 (1H, dd,J = 10.0, 2.6 Hz), 4.43 (2H, t, J = 6.6 Hz), 2.91 (2H, t, J = 6.6 Hz).544 (optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.67 (1H, m), 7.62 (1H, d, J = 0.7 Hz), 7.57 (1H,d, J = 0.7 Hz), 7.42-7.38 (1H, m), 7.31-7.20 (3H, m), 7.00 (1H, dd, J =0.5, 2.4 Hz), 4.17 (2H, s), 3.47 (1H, br s), 2.98 (1H, br s), 1.74- 1.25(10H, m). 545 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J = 0.7 Hz), 7.67- 7.63 (2H, m),7.42-7.38 (2H, m), 7.35-7.30 (3H, m), 7.21-7.16 (1H, m), 4.47- 4.43 (1H,m), 4.17-4.09 (1H, m), 3.20-3.13 (1H, m), 3.09-3.02 (1H, m), 2.04- 1.71(6H, m), 1.45-1.22 (3H, m).

TABLE 1-80 compound No. structural formula NMR 546 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, d, J = 0.7 Hz), 7.64- 7.58 (1H, m), 7.60(1H, s), 7.43-7.40 (1H, m), 7.32- 7.23 (3H, m), 7.16 (1H, d, J = 2.2Hz), 7.14-7.13 (1H, m), 4.70-4.65 (1H, m), 4.57-4.50 (1H, m), 3.51- 3.37(2H, m), 2.48-2.39 (1H, m), 2.38 (3H, s), 2.21-2.03 (2H, m), 1.99- 1.89(1H, m), 1.88-1.78 (1H, m), 1.74-1.63 (1H, m), 1.57-1.47 (1H, m). 547

¹H-NMR (DMSO-D₆) δ: 7.87 (1H, d, J = 0.7 Hz), 7.67- 7.60 (2H, m), 7.59(1H, d, J = 0.7 Hz), 7.41-7.22 (6H, m), 4.47 (1H, s), 3.96 (2H, s),2.16-2.12 (2H, m), 1.60-1.41 (12H, m). 548 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, s), 7.67 (1H, s), 7.66-7.62 (1H, m), 7.41-7.37 (2H, m), 7.36-7.27 (3H, m), 7.20 (1H, dd, J = 10.0, 2.5 Hz),4.71-4.66 (1H, m), 4.58-4.51 (1H, m), 3.51-3.38 (2H, m), 2.48- 2.37 (1H,m), 2.21-2.04 (2H, m), 1.99-1.89 (1H, m), 1.88-1.78 (1H, m), 1.74- 1.63(1H, m), 1.57-1.47 (1H, m). 549 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.43 (1H, br s), 8.12 (1H, s), 7.69 (1H, d, J = 0.9Hz), 7.66-7.62 (1H, m), 7.42- 7.38 (2H, m), 7.36-7.31 (2H, m), 7.27-7.24(1H, m), 7.19 (1H, dd, J = 9.9, 2.6 Hz), 5.00-4.94 (1H, m), 3.28-3.19(1H, m), 2.27- 2.05 (3H, m), 1.94-1.74 (3H, m). 550 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 13.17 (1H, br s), 7.97 (1H, d, J = 0.7 Hz),7.63-7.60 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.43 (1H, m),7.38-7.34 (1H, m), 7.32- 7.27 (1H, m), 7.26-7.22 (1H, m), 7.17 (1H, s),7.14-7.12 (1H, m), 5.06 (2H, s), 2.39 (3H, s). 551 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 13.22 (1H, br s), 8.07 (1H, d, J = 0.7 Hz), 7.69(1H, d, J = 0.7 Hz), 7.66-7.62 (1H, m), 7.43-7.38 (3H, m), 7.36- 7.31(1H, m), 7.30-7.25 (1H, m), 7.18 (1H, dd, J = 9.9, 2.4 Hz), 5.07 (2H,s).

TABLE 1-81 compound No. structural formula NMR 552 (optically activeform)

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.43 (1H, s), 7.30 (1H, d, J = 0.7Hz), 7.25- 7.14 (3H, m), 7.12-7.09 (1H, m), 6.70 (1H, d, J = 2.6 Hz),4.05-3.93 (2H, m), 3.90 (3H, s), 2.37 (2H, t, J = 6.6 Hz), 1.88-1.73(4H, m). 553 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.17 (1H, br s), 8.05 (1H, d, J = 0.7 Hz), 7.62(1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.31-7.19 (4H, m), 7.16- 7.13(1H, m), 6.85 (1H, d, J = 2.3 Hz), 4.64-4.57 (1H, m), 4.07 (2H, t, J =6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01-1.94 (2H, m), 1.52 (3H, d, J =6.5 Hz), 1.51 (3H, d, J = 6.5 Hz). 554 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 8.02 (1H, d, J = 0.7 Hz), 7.61(1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.30-7.20 (4H, m), 7.13 (1H, d,J = 1.9 Hz), 6.83 1H, d, J = 2.6 Hz), 4.24 (2H, q, J = 7.3 Hz), 4.06(2H, t, J = 6.4 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00- 1.93 (2H, m), 1.46(3H, t, J = 7.3 Hz). 555

¹H-NMR (DMSO-D₆) δ: 7.88 (1H, d, J = 7.9 Hz), 7.86 (1H, d, J = 7.7 Hz),7.66- 7.62 (1H, m), 7.53-7.47 (2H, m), 7.41-7.35 (2H, m), 7.28 (1H, s),3.72 (3H, s), 2.26 (3H, s), 2.17 (3H, s). 556

¹H-NMR (DMSO-D₆) δ: 7.87- 7.84 (1H, m), 7.83-7.82 (1H, m), 7.79-7.77(1H, m), 7.72-7.67 (1H, m), 7.58- 7.53 (1H, m), 7.48-7.43 (1H, m), 7.35(1H, s), 5.56 (1H, t, J = 5.5 Hz), 4.95- 4.85 (2H, m), 4.39-4.24 (2H,m), 4.16-3.99 (2H, m), 2.34-2.25 (2H, m). 557

¹H-NMR (DMSO-D₆) δ: 7.95 (1H, s), 7.66-7.56 (3H, m), 7.35-7.28 (3H, m),7.22- 7.18 (2H, m), 5.35 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.7 Hz),3.96 (3H, s). 558

¹H-NMR (DMSO-D₆) δ: 12.25 (1H, br s), 7.94 (1H, d, J = 0.5 Hz), 7.58(1H, d, J = 0.7 Hz), 7.57-7.54 (1H, m), 7.27-7.15 (4H, m), 7.11 (1H, s),6.77 (1H, d, J = 2.3 Hz), 3.94 (3H, s), 3.77-3.69 (2H, m), 2.90- 2.81(2H, m), 2.48-2.40 (1H, m), 1.96-1.88 (2H, m), 1.70-1.59 (2H, m).

TABLE 1-82 compound No. structural formula NMR 559

¹H-NMR (DMSO-D₆) δ: 7.72- 7.67 (1H, m), 7.63 (1H, d, J = 7.2 Hz), 7.57(1H, d, J = 7.9 Hz), 7.50-7.33 (5H, m), 7.23-7.19 (1H, m), 6.29-6.28(1H, m), 5.30 (2H, s), 3.62 (1H, br s). 560

¹H-NMR (CDCl₃) δ: 7.90-7.86 (2H, m), 7.77-7.72 (2H, m), 7.65 (1H, d, J =8.3 Hz), 7.62-7.59 (1H, m), 7.54 (1H, d, J = 1.5 Hz), 7.51- 7.45 (1H,m), 7.41-7.35 (1H, m), 6.40 (1H, dd, J = 2.4, 1.7 Hz), 3.86 (1H, s). 561(optically active form)

¹H-NMR (DMSO-D₆) δ: 8.90- 8.82 (2H, m), 8.29-8.16 (1H, m), 7.90-7.75(1H, m), 7.63 (1H, d, J = 6.4 Hz), 7.31-7.13 (5H, m), 7.01- 7.00 (1H,m), 6.62 (1H, d, J = 7.9 Hz), 4.10 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J =7.2 Hz), 1.98 (2H, t, J = 7.0 Hz). 562

¹H-NMR (DMSO-D₆) δ: 8.91 (1H, d, J = 2.1 Hz), 8.40 (1H, s), 8.14 (1H, d,J = 1.4 Hz), 8.07 (1H, s), 7.89-7.86 (1H, m), 7.74- 7.71 (1H, m),7.62-7.58 (1H, m), 7.54-7.49 (1H, m), 7.50 (1H, s), 3.90 (3H, s). 563

¹H-NMR (DMSO-D₆) δ: 8.92 (1H, d, J = 1.8 Hz), 8.41 (1H, s), 8.16-8.14(1H, m), 8.09 (1H, s), 7.89-7.86 (1H, m), 7.74-7.71 (1H, m), 7.62-7.58(1H, m), 7.54- 7.48 (1H, m), 7.50 (1H, s), 4.95 (1H, t, J = 5.3 Hz),4.19 (2H, t, J = 5.5 Hz), 3.79 (2H, dt, J = 5.5, 5.3 Hz). 564

¹H-NMR (DMSO-D₆) δ: 9.90 (1H, s), 7.92 (1H, s), 7.58-7.53 (1H, m), 7.56(1H, d, J = 0.7 Hz), 7.27- 7.17 (3H, m), 7.13 (1H, s), 7.05-7.01 (1H,m), 6.64 (1H, d, J = 2.2 Hz), 3.94 (3H, s). 565 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz),7.66- 7.62 (1H, m), 7.44-7.29 (5H, m), 7.17 (1H, dd, J = 9.9, 2.6 Hz),5.06 (1H, d, J = 5.3 Hz), 4.79 (1H, t, J = 5.6 Hz), 4.33 (1H, dd, J =13.8, 4.1 Hz), 4.11 (1H, dd, J = 13.7, 7.7 Hz), 3.95-3.87 (1H, m), 3.46-3.35 (2H, m).

TABLE 1-83 compound No. structural formula NMR 566 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, s), 7.68 (1H, s), 7.66-7.62 (1H, m), 7.45-7.29 (5H, m), 7.16 (1H, dd, J = 9.9, 2.4 Hz), 5.07 (1H, d, J = 5.5 Hz),4.79 (1H, t, J = 5.5 Hz), 4.34 (1H, dd, J = 13.7, 4.0 Hz), 4.10 (1H, dt,J = 13.7, 7.9 Hz), 3.95-3.86 (1H, m), 3.47- 3.35 (2H, m). 567

¹H-NMR (DMSO-D₆) δ: 7.63 (2H, d, J = 7.9 Hz), 7.42 (1H, t, J = 7.5 Hz),7.36- 7.28 (2H, m), 7.26-7.18 (2H, m), 6.90-6.85 (1H, m), 3.79 (1.3H,s), 3.78 (1.7H, s), 2.07 (1.3H, s), 1.97 (1.7H, s), 1.95 (1.7H, s), 1.86(1.3H, s). 568

¹H-NMR (DMSO-D₆) δ: 8.91 (1H, d, J = 2.0 Hz), 8.44 (1H, s), 8.16-8.13(1H, m), 8.09 (1H, s), 7.89-7.86 (1H, m), 7.74-7.70 (1H, m), 7.62-7.57(1H, m), 7.54- 7.49 (2H, m), 4.36 (2H, t, J = 6.7 Hz), 2.84 (2H, t, J =6.6 Hz). 569

¹H-NMR (DMSO-D₆) δ: 7.95 (1H, s), 7.59 (1H, d, J = 0.7 Hz), 7.58-7.55(1H, m), 7.28-7.19 (3H, m), 7.19- 7.16 (1H, m), 7.13 (1H, s), 6.78 (1H,d, J = 2.3 Hz), 3.95 (3H, s), 3.78-3.73 (4H, m), 3.21-3.17 (4H, m). 570

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, s), 7.91 (1H, s), 7.82-7.78 (1H, m), 7.75-7.73 (1H, m), 7.72-7.70 (1H, m), 7.68-7.63 (1H, m), 7.54-7.48 (1H, m),7.40- 7.34 (1H, m), 7.22 (1H, s), 5.47 (1H, t, J = 5.3 Hz), 4.87 (2H, d,J = 5.3 Hz), 3.89 (3H, s). 571

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 3.1 Hz), 7.62- 7.57 (2H, m),7.33-7.18 (4H, m), 7.17-7.13 (1H, m), 6.84-6.80 (1H, m), 5.00- 4.97 (1H,m), 4.72-4.67 (1H, m), 4.11-4.05 (1H, m), 3.98-3.89 (4H, m), 3.86- 3.77(1H, m), 3.49-3.42 (2H, m). 572

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.7 Hz), 7.72 (1H, d, J = 1.5 Hz),7.71- 7.66 (2H, m), 7.58-7.53 (1H, m), 7.47-7.42 (1H, m), 7.33 (1H, s),5.54 (1H, t, J = 5.5 Hz), 4.95-4.85 (2H, m), 3.50 (2H, t, J = 6.6 Hz),3.47-3.38 (2H, m), 1.94-1.80 (4H, m).

TABLE 1-84 compound No. structural formula NMR 573 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.61 (1H, d, J = 0.7 Hz), 7.60-7.57(1H, m), 7.29-7.22 (4H, m), 7.12 (1H, d, J = 1.9 Hz), 6.80 (1H, d, J =2.3 Hz), 4.12 (2H, t, J = 6.1 Hz), 3.95 (3H, s), 3.07 (2H, t, J = 7.5Hz), 2.22-2.15 (2H, m). 574 (optically active form)

¹H-NMR (CDCl₃) δ: 7.77 (1H, d, J = 0.7 Hz), 7.76 (1H, d, J = 0.7 Hz),7.70-7.66 (1H, m), 7.54-7.51 (1H, m), 7.29-7.18 (4H, m), 7.13 (1H, dd, J= 1.5, 0.8 Hz), 2.44 (3H, s), 1.97 (6H, s). 575 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.53 (1H, br s), 7.85 (1H, d, J = 0.7 Hz),7.64-7.60 (1H, m), 7.59 (1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m),7.32-7.20 (3H, m), 7.17 (1H, s), 7.10 (1H, dd, J = 1.7, 0.8 Hz), 4.35(2H, s), 2.38 (3H, s), 1.17 (6H, s). 576 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 8.04 (1H, d, J = 0.7 Hz),7.63-7.57 (1H, m), 7.58 (1H, d, J = 0.7 Hz), 7.43-7.40 (1H, m),7.32-7.26 (3H, m), 7.15 (1H, s), 7.13 (1H, d, J = 0.9 Hz), 2.94 (2H, s),2.38 (3H, s), 1.70 (3H, s), 1.69 (3H, s). 577 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.21 (1H, br s), 7.98 (1H, s), 7.62-7.57 (1H, m),7.61 (1H, d, J = 0.7 Hz), 7.29- 7.21 (4H, m), 7.14-7.12 (1H, m), 6.82(1H, d, J = 2.6 Hz), 4.07 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 2.60-2.54(1H, m), 2.11- 2.01 (1H, m), 1.85-1.75 (1H, m), 1.15 (3H, d, J = 6.7Hz). 578

¹H-NMR (CDCl₃) δ: 8.42 (1H, d, J = 7.5 Hz), 7.78-7.77 (1H, m), 7.76-7.70(2H, m), 7.69-7.68 (1H, m), 7.67 (1H, d, J = 1.5 Hz), 7.54- 7.48 (1H,m), 7.42-7.36 (1H, m), 3.94 (3H, s), 3.53 (1H, s), 3.09 (1H, br s). 579

¹H-NMR (DMSO-D₆) δ: 8.29 (1H, s), 8.00 (1H, s), 7.94 (1H, d, J = 0.7Hz), 7.77- 7.74 (1H, m), 7.67-7.61 (2H, m), 7.50 (1H, d, J = 1.8 Hz),7.34-7.30 (3H, m), 7.25 (1H, s), 3.97 (3H, s), 3.87 (3H, s).

TABLE 1-85 compound No. structural formula NMR 580

¹H-NMR (DMSO-D₆) δ: 8.30 (1H, d, J = 0.7 Hz), 8.01 (1H, d, J = 0.7 Hz),7.97 (1H, d, J = 0.7 Hz), 7.78- 7.75 (1H, m), 7.67 (1H, d, J = 0.7 Hz),7.66-7.62 (1H, m), 7.53 (1H, d, J = 1.6 Hz), 7.39-7.27 (3H, m), 7.26(1H, s), 5.00 (1H, t, J = 5.2 Hz), 4.95 (1H, t, J = 5.3 Hz), 4.28 (2H,t, J = 5.7 Hz), 4.18 (2H, t, J = 5.7 Hz), 3.85 (2H, dt, J = 5.2, 5.7Hz), 3.79 (2H, dt, J = 5.2, 5.7 Hz). 581 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, s), 7.63 (1H, d, J = 0.7 Hz), 7.61-7.57(1H, m), 7.30-7.20 (4H, m), 7.13- 7.11 (1H, m), 6.80 (1H, d, J = 2.6Hz), 4.42 (2H, t, J = 6.6 Hz), 4.10 (2H, q, J = 7.0 Hz), 2.90 (2H, t, J= 6.7 Hz). 582 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.20 (1H, br s), 8.01 (1H, s), 7.63 (1H, d, J = 0.7Hz), 7.62-7.56 (1H, m), 7.28- 7.19 (4H, m), 7.14-7.11 (1H, m), 6.83 (1H,d, J = 2.3 Hz), 4.23 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.0 Hz), 2.27(2H, t, J = 7.3 Hz), 2.12-2.05 (2H, m), 1.35 (3H, t, J = 7.0 Hz). 583

¹H-NMR (DMSO-D₆) δ: 7.69- 7.66 (1H, m), 7.63-7.60 (1H, m), 7.49-7.45(1H, m), 7.33-7.29 (1H, m), 7.20 (1H, s), 7.14 (1H, d, J = 2.6 Hz),7.09-7.07 (1H, m), 5.47 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m), 4.15(2H, t, J = 5.6 Hz), 3.58 (2H, t, J = 5.4 Hz), 3.48 (2H, t, J = 7.2 Hz),2.23 (2H, t, J = 8.1 Hz), 1.98- 1.88 (2H, m). 854

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, d, J = 0.9 Hz), 7.94 (1H, d, J = 0.7 Hz),7.81 (1H, d, J = 7.7 Hz), 7.69- 7.64 (2H, m), 7.57-7.55 (1H, m),7.54-7.49 (1H, m), 7.39-7.35 (1H, m), 7.19 (1H, s), 4.94 (1H, t, J = 5.3Hz), 4.18 (2H, t, J = 5.6 Hz), 3.78 (2H, dt, J = 5.6, 5.3 Hz), 2.65 (3H,s). 855

¹H-NMR (DMSO-D₆) δ: 8.39 (1H, d, J = 0.7 Hz), 8.08 (1H, d, J = 0.7 Hz),8.05 (1H, d, J = 1.6 Hz), 7.95- 7.93 (1H, m), 7.78-7.75 (1H, m),7.68-7.65 (1H, m), 7.47-7.43 (1H, m), 7.42- 7.38 (1H, m), 7.35 (1H, s),4.96 (1H, t, J = 5.4 Hz), 4.19 (2H, t, J = 5.6 Hz), 3.79 (2H, dt, J =5.6, 5.4 Hz), 2.77 (3H, s).

TABLE 1-86 compound No. structural formula NMR 586

¹H-NMR (DMSO-D₆) δ: 8.25- 8.23 (1H, m), 7.91-7.78 (3H, m), 7.71-7.65(2H, m), 7.54-7.49 (1H, m), 7.39- 7.34 (1H, m), 7.21 (1H, s), 5.51-5.47(1H, m), 5.46- 5.35 (1H, m), 4.94 (1H, t, J = 5.3 Hz), 4.19 (2H, t, J =5.7 Hz), 3.81-3.75 (2H, m), 1.50-1.43 (3H, m). 587

¹H-NMR (DMSO-D₆) δ: 8.44 (1H, s), 8.07 (1H, d, J = 0.5 Hz), 8.05 (1H, d,J = 1.6 Hz), 7.95-7.93 (1H, m), 7.78-7.75 (1H, m), 7.68- 7.65 (1H, m),7.47-7.43 (1H, m), 7.42-7.38 (1H, m), 7.34 (1H, s), 4.18 (2H, q, J = 7.3Hz), 2.77 (3H, s), 1.43 (3H, t, J = 7.3 Hz). 588 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.45 (1H, br s), 8.00 (1H, s), 7.64 (1H, d, J = 0.7Hz), 7.62-7.58 (1H, m), 7.31- 7.20 (4H, m), 7.16-7.14 (1H, m), 6.84 (1H,d, J = 2.6 Hz), 4.43 (2H, t, J = 6.7 Hz), 3.84 (3H, s), 2.91 (2H, t, J =6.7 Hz). 589 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.22 (1H, br s), 8.02 (1H, s), 7.64 (1H, s),7.62-7.57 (1H, m), 7.30-7.18 (4H, m), 7.16-7.13 (1H, m), 6.86 (1H, d, J= 2.1 Hz), 4.24 (2H, t, J = 6.8 Hz), 3.84 (3H, s), 2.28 (2H, t, J = 7.3Hz), 2.13-2.06 (2H, m). 590

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, d, J = 0.7 Hz), 7.95 (1H, d, J = 0.9 Hz),7.82- 7.81 (1H, m), 7.79 (1H, d, J = 7.9 Hz), 7.73 (1H, dd, J = 8.0, 1.7Hz), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.22 (1H, s), 5.44 (1H, t, J= 5.4 Hz), 4.94 (1H, t, J = 5.4 Hz), 4.91-4.81 (2H, m), 4.18 (2H, t, J =5.6 Hz), 3.78 (2H, dt, J = 5.6, 5.4 Hz). 591

¹H-NMR (DMSO-D₆) δ: 8.75 (1H, d, J = 7.9 Hz), 8.28 (1H, s), 7.92 (1H, d,J = 0.9 Hz), 7.71-7.69 (1H, m), 7.65 (1H, d, J = 1.5 Hz), 7.64-7.61 (1H,m), 7.48- 7.43 (1H, m), 7.35-7.30 (1H, m), 7.14 (1H, s), 5.40 (1H, s),3.89 (3H, s), 1.73 (3H, s), 1.63 (3H, s). 592

¹H-NMR (DMSO-D₆) δ: 8.75 (1H, d, J = 7.9 Hz), 8.27 (1H, d, J = 0.7 Hz),7.94 (1H, d, J = 0.7 Hz), 7.72- 7.70 (1H, m), 7.65 (1H, d, J = 1.6 Hz),7.65-7.61 (1H, m), 7.48-7.43 (1H, m), 7.35-7.30 (1H, m), 7.14 (1H, s),5.41 (1H, s), 4.94 (1H, t, J = 5.3 Hz), 4.18 (2H, t, J = 5.6 Hz), 3.79(2H, q, J = 5.6 Hz), 1.73 (3H, s), 1.64 (3H, s).

TABLE 1-87 compound No. structural formula NMR 593

¹H-NMR (DMSO-D₆) δ: 8.35 (1H, s), 7.94 (1H, s), 7.85-7.82 (1H, m), 7.78(1H, d, J = 8.1 Hz), 7.73 (1H, dd, J = 8.1, 1.6 Hz), 7.58-7.51 (2H, m),7.37- 7.33 (1H, m), 7.21 (1H, s), 5.44 (1H, t, J = 5.3 Hz), 4.90-4.81(2H, m), 4.57- 4.50 (1H, m), 1.47 (3H, s), 1.46 (3H, s). 594

¹H-NMR (DMSO-D₆) δ: 12.42 (1H, br s), 8.42 (1H, d, J = 0.7 Hz), 8.08(1H, d, J = 0.9 Hz), 8.04 (1H, d, J = 1.5 Hz), 7.94-7.92 (1H, m),7.78-7.75 (1H, m), 7.68- 7.65 (1H, m), 7.47-7.43 (1H, m), 7.42-7.38 (1H,m), 7.35 (1H, s), 4.36 (2H, t, J = 6.7 Hz), 3.39 (3H, t, J = 6.9 Hz),2.87 (2H, t, J = 6.7 Hz), 2.77 (3H, s). 595 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, d, J = 0.5 Hz), 7.68 (1H, d, J = 0.5 Hz),7.65- 7.61 (1H, m), 7.44-7.37 (2H, m), 7.40 (1H, s), 7.36-7.25 (2H, m),7.18 (1H, dd, J = 10.0, 2.6 Hz), 4.97 (2H, t, J = 5.3 Hz), 4.39-4.32(1H, m), 3.86- 3.76 (4H, m). 596

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, s), 8.06 (1H, d, J = 0.5 Hz), 8.04 (1H, d,J = 1.6 Hz), 7.94-7.91 (1H, m), 7.76 (1H, d, J = 7.4 Hz), 7.68-7.64 (1H,m), 7.48- 7.43 (1H, m), 7.42-7.38 (1H, m), 7.35 (1H, s), 3.90 (3H, s),2.77 (3H, s). 597

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 0.5 Hz), 7.94 (1H, d, J = 0.7 Hz),7.82 (1H, br s), 7.79 (1H, d, J = 8.1 Hz), 7.72 (1H, dd, J = 8.1, 1.6Hz), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.22 (1H, s), 5.44 (1H, t, J= 5.4 Hz), 4.90-4.81 (2H, m), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J =7.3 Hz). 598

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, d, J = 4.4 Hz), 7.90- 7.79 (3H, m),7.69-7.65 (2H, m), 7.54-7.49 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s),5.48 (1H, br s), 5.44 (0.5H, q, J = 6.3 Hz), 5.38 (0.5H, q, J = 6.4 Hz),3.89 (3H, s), 1.48 (1.6H, d, J = 6.3 Hz), 1.45 (1.4H, d, J = 6.3 Hz).599

¹H-NMR (CDCl₃) δ: 7.82-7.80 (1H, m), 7.71-7.66 (1H, m), 7.43-7.35 (2H,m), 7.35- 7.29 (1H, m), 7.11 (1H, d, J = 2.3 Hz), 4.16 (2H, t, J = 5.3Hz), 3.70 (1H, br s), 3.64 (2H, t, J = 5.2 Hz), 3.57 (2H, t, J = 7.0Hz), 2.68 (3H, s), 2.34 (2H, t, J = 8.0 Hz), 2.08-1.98 (2H, m).

TABLE 1-88 compound No. structural formula NMR 600

¹H-NMR (DMSO-D₆) δ: 8.29 (1H, s), 7.96 (1H, s), 7.82-7.77 (2H, m), 7.72(1H, dd, J = 8.0, 1.7 Hz), 7.58-7.52 (2H, m), 7.37- 7.33 (1H, m), 4.88(1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.36 (2H, t, J = 6.7Hz), 2.86 (2H, t, J = 6.7 Hz). 601

¹H-NMR (DMSO-D₆) δ: 8.23 (1H, d, J = 0.5 Hz), 7.95 (1H, d, J = 0.7 Hz),7.80- 7.77 (2H, m), 7.71 (1H, dd, J = 8.0, 1.7 Hz), 7.57-7.52 (2H, m),7.42 (1H, br s), 7.37-7.33 (1H, m), 7.23 (1H, s), 6.92 (1H, br s), 5.44(1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 4.34 (2H, t, J = 6.8 Hz), 2.67(2H, t, J = 7.0 Hz). 602

¹H-NMR (DMSO-D₆) δ: 8.39 (1H, s), 7.95 (1H, s), 7.88-7.86 (1H, m), 7.79-7.74 (2H, m), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.20 (1H, s), 5.44(1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 1.58 (9H, s). 603

¹H-NMR (DMSO-D₆) δ: 8.39- 8.36 (1H, m), 8.34 (1H, d, J = 0.4 Hz), 7.99(1H, d, J = 0.9 Hz), 7.81-7.79 (1H, m), 7.75 (1H, d, J = 1.5 Hz),7.69-7.66 (1H, m), 7.56-7.52 (1H, m), 7.45- 7.41 (1H, m), 7.35 (1H, s),5.56 (1H, t, J = 6.0 Hz), 4.50 (2H, d, J = 6.0 Hz), 3.87 (3H, s). 604(optically active form)

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.63 (1H, d, J = 7.3Hz), 7.38 (1H, br s), 7.31-7.21 (3H, m), 7.04 (1H, d, J = 2.4 Hz),6.63-6.59 (1H, m), 4.11 (2H, t, J = 6.5 Hz), 2.41 (2H, t, J = 7.3 Hz),2.01-1.94 (2H, m). 605 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 0.7 Hz), 7.63- 7.59 (1H, m), 7.61(1H, d, J = 0.7 Hz), 7.42 (1H, s), 7.37 (1H, dd, J = 6.7, 0.9 Hz),7.32-7.22 (2H, m), 7.16 (1H, s), 7.14 (1H, dd, J = 1.6, 0.7 Hz), 4.96(2H, td, J = 5.3, 1.2 Hz), 4.38- 4.32 (1H, m), 3.86-3.76 (4H, m), 2.39(3H, s). 606 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.07 (1H, br s), 7.99 (1H, d, J = 0.7 Hz),7.64-7.60 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.42 (1H, s), 7.32- 7.21(3H, m), 7.17 (1H, s), 7.12 (1H, dd, J = 1.5, 0.8 Hz), 4.21 (2H, t, J =6.7 Hz), 2.38 (3H, s), 2.28 (2H, t, J = 7.4 Hz), 1.91- 1.84 (2H, m),1.55-1.48 (2H, m).

TABLE 1-89 compound No. structural formula NMR 607 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 12.53 (1H, br s), 7.94 (1H, d, J = 0.7 Hz), 7.67(1H, d, J = 0.7 Hz), 7.65 (1H, d, J = 7.0 Hz), 7.43-7.39 (2H, m),7.37-7.24 (3H, m), 7.17 (1H, dd, J = 10.0, 2.6 Hz), 4.36 (2H, s), 1.18(6H, s). 608

¹H-NMR (DMSO-D₆) δ: 13.15 (1H, br s), 8.29 (1H, s), 7.99 (1H, d, J = 0.5Hz), 7.83-7.79 (2H, m), 7.74 (1H, dd, J = 8.1, 1.6 Hz), 7.58-7.52 (2H,m), 7.38- 7.33 (1H, m), 7.24 (1H, s), 5.45 (1H, t, J = 5.3 Hz), 5.00(2H, s), 4.91-4.82 (2H, m). 609

¹H-NMR (DMSO-D₆) δ: 8.27- 8.25 (1H, m), 7.98-7.96 (1H, m), 7.84-7.79(2H, m), 7.76-7.72 (1H, m), 7.58- 7.51 (3H, m), 7.38-7.33 (1H, m), 7.31(1H, br s), 7.24 (1H, d, J = 1.9 Hz), 5.47-5.43 (1H, m), 4.87- 4.86 (2H,m), 4.80 (2H, d, J = 1.6 Hz). 610 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.19 (1H, br s), 8.14 (1H, d, J = 0.7 Hz), 7.66(1H, s), 7.65-7.61 (1H, m), 7.41- 7.37 (2H, m), 7.37-7.29 (3H, m), 7.18(1H, dd, J = 10.0, 2.6 Hz), 2.94 (2H, s), 1.70 (3H, s), 1.69 (3H, s).611

¹H-NMR (DMSO-D₆) δ: 7.67 (1H, d, J = 7.7 Hz), 7.61 (1H, d, J = 7.4 Hz),7.49- 7.44 (1H, m), 7.32-7.28 (1H, m), 7.19 (1H, s), 7.13 (1H, d, J =2.3 Hz), 7.07- 7.05 (1H, m), 5.46 (1H, t, J = 5.4 Hz), 4.87-4.78 (2H,m), 4.47 (1H, t, J = 5.2 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.47 (2H, dd, J= 11.6, 6.5 Hz), 1.82-1.75 (2H, m), 1.63-1.55 (2H, m). 612

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.86 (1H, d, J = 7.6 Hz), 7.72 (1H,br s), 7.61 (1H, d, J = 7.4 Hz), 7.46-7.41 (1H, m), 7.35- 7.29 (1H, m),7.30 (1H, s), 7.25-7.23 (1H, m), 7.07 (1H, d, J = 2.5 Hz), 4.23 (2H, t,J = 5.7 Hz), 4.20- 4.16 (2H, m), 3.67-3.59 (2H, m), 3.46 (2H, t, J = 6.4Hz), 1.98-1.92 (2H, m). 613

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 8.64 (1H, s), 7.64 (1H, d, J = 7.4Hz), 7.59 (1H, s), 7.40-7.31 (3H, m), 7.30-7.28 (1H, m), 7.13 (1H, d, J= 2.6 Hz), 7.06 (1H, d, J = 7.0 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.42 (2H,t, J = 7.3 Hz), 2.01-1.94 (2H, m).

TABLE 1-90 compound No. structural formula NMR 614 (optically activeform)

¹H-NMR (CDCl₃) δ: 7.71 (2H, s), 7.68-7.64 (1H, m), 7.25-7.22 (3H, m),7.11- 7.08 (1H, m), 6.80-6.79 (1H, m), 3.88 (3H, s), 3.15 (2H, s), 2.79(1H, s), 1.78 (3H, s), 1.77 (3H, s). 615

¹H-NMR (DMSO-D₆) δ: 8.25 (1H, s), 7.93 (1H, s), 7.80 (1H, d, J = 7.7Hz), 7.76- 7.74 (1H, m), 7.73-7.71 (1H, m), 7.67-7.64 (1H, m), 7.53-7.49(1H, m), 7.39- 7.34 (1H, m), 7.23 (1H, s), 5.47 (1H, t, J = 5.3 Hz),4.95 (1H, t, J = 5.3 Hz), 4.91-4.83 (2H, m), 4.19 (2H, t, J = 5.6 Hz),3.78 (2H, q, J = 5.5 Hz). 616

¹H-NMR (CDCl₃) δ: 8.28-8.25 (1H, m), 7.88 (1H, d, J = 2.0 Hz), 7.84-7.82(1H, m), 7.73-7.69 (1H, m), 7.51- 7.46 (1H, m), 7.44-7.40 (1H, m), 4.01(3H, s), 2.83 (1H, br s). 617 (optically active form)

¹H-NMR (CDCl₃) δ: 8.30-8.27 (1H, m), 7.89 (1H, d, J = 2.0 Hz), 7.84-7.82(1H, m), 7.73-7.70 (1H, m), 7.52- 7.47 (1H, m), 7.44-7.40 (1H, m), 4.02(3H, s), 2.77 (1H, br s). 618

¹H-NMR (DMSO-D₆) δ: 8.31 (1H, d, J = 0.7 Hz), 7.92 (1H, d, J = 0.7 Hz),7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.4 Hz), 7.73- 7.71 (1H, m),7.67-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.22 (1H, s),5.47 (1H, t, J = 5.4 Hz), 4.91-4.82 (2H, m), 4.18 (2H, q, J = 7.3 Hz),1.42 (3H, t, J = 7.3 Hz). 619 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.55 (1H, br s), 7.89 (1H, d, J = 0.7 Hz), 7.63(1H, d, J = 0.7 Hz), 7.62-7.59 (1H, m), 7.28-7.24 (3H, m), 7.21- 7.15(2H, m), 6.83 (1H, d, J = 2.3 Hz), 4.36 (2H, s), 3.84 (3H, s), 1.19 (6H,s). 620

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.58 (2H, m), 7.60(1H, d, J = 0.7 Hz), 7.38-7.26 (3H, m), 7.24-7.21 (1H, m), 7.19 (1H, brs), 5.35 (1H, t, J = 5.6 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.57 (2H, d, J =5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.6, 5.6 Hz).

TABLE 1-91 compound No. structural formula NMR 621

¹H-NMR (DMSO-D₆) δ: 8.34 (1H, s), 7.91 (1H, s), 7.80 (1H, d, J = 7.7Hz), 7.76- 7.75 (1H, m), 7.75-7.73 (1H, m), 7.68-7.64 (1H, m), 7.53-7.48(1H, m), 7.39- 7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.4 Hz),4.91-4.82 (2H, m), 4.59- 4.49 (1H, m), 1.48 (3H, s), 1.46 (3H, s). 622

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, d, J =0.7 Hz), 7.31-7.22 (4H, m), 7.17- 7.13 (1H, m), 6.82 (1H, d, J = 2.6Hz), 4.56 (2H, t, J = 5.2 Hz), 4.04 (2H, d, J = 6.0 Hz), 3.95 (3H, s),3.58-3.48 (4H, m), 2.04- 1.95 (1H, m). 623

¹H-NMR (DMSO-D₆) δ: 12.20 (1H, br s), 7.98 (1H, d, J = 0.5 Hz),7.65-7.58 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.34-7.20 (5H, m), 5.35(1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.3 Hz), 4.24 (2H, t, J = 6.8 Hz),2.27 (2H, t, J = 7.4 Hz), 2.12-2.05 (2H, m). 624 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.63 (1H, d, J = 0.7 Hz),7.61- 7.56 (1H, m), 7.34-7.29 (1H, m), 7.28-7.23 (2H, m), 7.21 (1H, s),7.14-7.11 (1H, m), 6.82 (1H, d, J = 2.3 Hz), 4.97 (1H, t, J = 5.2 Hz),4.46 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.7 Hz), 4.05 (2H, t, J = 6.5Hz), 3.85-3.79 (2H, m), 3.49-3.43 (2H, m), 1.81- 1.74 (2H, m), 1.61-1.54(2H, m). 625

¹H-NMR (DMSO-D₆) δ: 7.89 (1H, d, J = 7.7 Hz), 7.74- 7.70 (1H, m),7.66-7.58 (3H, m), 7.52 (1H, s), 7.52-7.47 (1H, m), 4.54 (1H, d, J =18.8 Hz), 4.49 (1H, d, J = 18.8 Hz). 626

¹H-NMR (DMSO-D₆) δ: 8.10 (1H, br s), 7.85 (1H, d, J = 7.7 Hz), 7.72 (1H,br s), 7.63-7.59 (1H, m), 7.45- 7.40 (1H, m), 7.34-7.29 (1H, m), 7.30(1H, s), 7.23-7.21 (1H, m), 7.04 (1H, d, J = 2.6 Hz), 3.86 (3H, s).

TABLE 1-92 compound No. structural formula NMR 627

¹H-NMR (DMSO-D₆) δ: 7.67 (1H, d, J = 7.9 Hz), 7.63- 7.60 (1H, m),7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.20 (1H, s), 7.14 (1H, d, J = 2.3Hz), 7.09-7.07 (1H, m), 5.48 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m),3.83 (3H, s). 628

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.61-7.57 (1H, m), 7.59 (1H, d, J =0.7 Hz), 7.30-7.18 (5H, m), 6.87 (1H, d, J = 2.4 Hz), 4.87- 4.82 (2H,m), 4.35-4.29 (1H, m), 3.95 (3H, s), 3.66-3.54 (4H, m). 629 (opticallyactive form)

¹H-NMR (DMSO-D₆) δ: 8.31 (1H, d, J = 0.7 Hz), 7.91 (1H, d, J = 0.9 Hz),7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.73- 7.71 (1H, m),7.67-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s),5.46 (1H, t, J = 5.4 Hz), 4.92-4.82 (2H, m), 4.18 (2H, q, J = 7.3 Hz),1.42 (3H, t, J = 7.3 Hz). 630 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, s), 8.14 (1H, br s), 7.98 (1H, d, J = 0.7Hz), 7.91 (1H, d, J = 7.7 Hz), 7.85-7.83 (1H, m), 7.74 (1H, br s), 7.70(1H, d, J = 1.5 Hz), 7.67-7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35(1H, m), 7.30 (1H, s), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3Hz). 631

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 0.9 Hz), 7.65- 7.60 (1H, m), 7.62(1H, d, J = 0.9 Hz), 7.42-7.35 (2H, m), 7.33-7.27 (2H, m), 7.17 (1H, s),7.09 (1H, d, J = 1.6 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.26 (2H, t, J = 5.7Hz), 3.83 (2H, q, J = 5.5 Hz), 2.60-2.47 (2H, m), 1.92-1.82 (1H, m),0.93 (3H, d, J = 6.7 Hz), 0.91 (3H, d, J = 6.5 Hz). 632

¹H-NMR (DMSO-D₆) δ: 8.22 (1H, br s), 7.95-7.92 (1H, m), 7.81 (1H, br s),7.73- 7.66 (2H, m), 7.58 (1H, d, J = 1.4 Hz), 7.53-7.48 (1H, m),7.47-7.42 (1H, m), 7.44 (1H, s), 4.41 (1H, s). 633

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.90 (1H, d, J = 7.7 Hz), 7.68 (1H,br s), 7.65-7.62 (1H, m), 7.55- 7.53 (1H, m), 7.47-7.43 (1H, m),7.39-7.34 (1H, m), 7.33 (1H, d, J = 1.6 Hz), 7.25 (1H, s), 2.71 (2H, q,J = 7.6 Hz), 1.23 (3H, t, J = 7.5 Hz).

TABLE 1-93 compound No. structural formula NMR 634

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, br s), 7.91 (1H, d, J = 7.7 Hz), 7.67 (1H,br s), 7.65-7.61 (1H, m), 7.55- 7.52 (1H, m), 7.47-7.42 (1H, m),7.38-7.32 (2H, m), 7.23 (1H, s), 2.71-2.63 (2H, m), 0.95 (9H, t, J = 7.9Hz), 0.92-0.86 (2H, m), 0.56 (6H, q, J = 7.9 Hz). 635

¹H-NMR (DMSO-D₆) δ: 7.78 (1H, d, J = 7.7 Hz), 7.70- 7.66 (1H, m),7.64-7.61 (1H, m), 7.57-7.52 (2H, m), 7.46-7.40 (1H, m), 7.41 (1H, s),5.62 (1H, t, J = 5.6 Hz), 4.93-4.82 (2H, m). 636

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, br s), 7.92-7.89 (1H, m), 7.86 (1H, br s),7.69- 7.64 (2H, m), 7.56 (1H, d, J = 2.1 Hz), 7.53-7.47 (1H, m), 7.49(1H, s), 7.46-7.41 (1H, m). 637

¹H-NMR (DMSO-D₆) δ: 8.22 (1H, s), 7.89 (1H, d, J = 0.8 Hz), 7.84 (1H, d,J = 7.7 Hz), 7.69-7.68 (1H, m), 7.67-7.63 (1H, m), 7.58 (1H, d, J = 1.6Hz), 7.55 (1H, br s), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 7.22 (1H,s), 7.09 (1H, br s), 3.89 (3H, s), 3.89 (1H, d, J = 15.7 Hz), 3.81 (1H,d, J = 15.7 Hz). 638

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, s), 7.93 (1H, s), 7.81 (1H, d, J = 7.7Hz), 7.78 (2H, s), 7.66 (1H, d, J = 7.4 Hz), 7.53-7.48 (1H, m),7.39-7.34 (1H, m), 7.20 (1H, s), 5.45 (1H, t, J = 5.4 Hz), 4.92-4.82(2H, m), 1.58 (9H, s). 639

¹H-NMR (DMSO-D₆) δ: 8.46 (1H, s), 8.13 (1H, br s), 7.99 (1H, s), 7.91(1H, d, J = 7.7 Hz), 7.89 (1H, br s), 7.78-7.73 (2H, m), 7.67-7.63 (1H,m), 7.49- 7.44 (1H, m), 7.40-7.34 (1H, m), 7.30 (1H, s), 1.57 (9H, s).640

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.85 (1H, d, J = 7.7 Hz), 7.71 (1H,br s), 7.63-7.59 (1H, m), 7.45- 7.40 (1H, m), 7.34-7.28 (1H, m), 7.30(1H, s), 7.24-7.21 (1H, m), 7.04 (1H, d, J = 2.3 Hz), 4.93 (1H, t, J =5.6 Hz), 4.09 (2H, t, J = 4.9 Hz), 3.75 (2H, q, J = 5.0 Hz).

TABLE 1-94 compound No. structural formula NMR 641

¹H-NMR (DMSO-D₆) δ: 7.84- 7.81 (1H, m), 7.71-7.65 (2H, m), 7.60-7.58(1H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.33 (1H, s), 5.53 (1H,t, J = 5.5 Hz), 4.91-4.81 (2H, m), 4.31 (1H, s). 642

¹H-NMR (DMSO-D₆) δ: 7.79- 7.75 (1H, m), 7.66-7.62 (1H, m), 7.52-7.46(1H, m), 7.42-7.38 (2H, m), 7.37- 7.33 (1H, m), 7.13 (1H, s), 5.40 (1H,t, J = 5.4 Hz), 4.88-4.78 (2H, m), 2.69 (2H, q, J = 7.6 Hz), 1.23 (3H,t, J = 7.5 Hz). 643

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, s), 7.91 (1H, d, J = 0.7 Hz), 7.83 (1H, d,J = 7.7 Hz), 7.68-7.64 (2H, m), 7.56-7.50 (2H, m), 7.40- 7.35 (1H, m),7.19 (1H, s), 4.91 (1H, t, J = 5.3 Hz), 3.88 (3H, s), 3.74-3.67 (2H, m),3.24-3.09 (2H, m). 644

¹H-NMR (DMSO-D₆) δ: 7.86 (1H, d, J = 7.7 Hz), 7.83- 7.81 (1H, m),7.79-7.77 (1H, m), 7.70 (1H, d, J = 7.5 Hz), 7.58-7.54 (1H, m),7.48-7.43 (1H, m), 7.35 (1H, s), 5.76 (1H, d, J = 6.2 Hz), 5.56 (1H, t,J = 5.5 Hz), 4.96-4.86 (2H, m), 4.56-4.43 (2H, m), 4.34- 4.24 (1H, m),4.11-4.00 (1H, m), 3.88-3.76 (1H, m). 645

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 0.7 Hz), 8.15 (1H, br s), 8.00 (1H,d, J = 0.7 Hz), 7.91 (1H, d, J = 7.7 Hz), 7.86-7.83 (1H, m), 7.75 (1H,br s), 7.70 (1H, d, J = 1.6 Hz), 7.67-7.63 (1H, m), 7.49-7.44 (1H, m),7.40-7.35 (1H, m), 7.31 (1H, s), 3.95 (2H, d, J = 7.2 Hz), 2.20-2.13(1H, m), 0.88 (3H, d, J = 1.2 Hz), 0.86 (3H, d, J = 1.4 Hz). 646

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, s), 8.15 (1H, br s), 8.00 (1H, s), 7.91(1H, d, J = 7.7 Hz), 7.86-7.84 (1H, m), 7.75 (1H, br s), 7.71 (1H, d, J= 1.6 Hz), 7.67- 7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m),7.31 (1H, s), 3.95 (2H, s), 0.94 (9H, s). 647 (optically active form)

¹H-NMR (CDCl₃) δ: 8.41-8.37 (1H, m), 8.24-8.22 (1H, m), 8.11 (1H, d, J =1.5 Hz), 7.79-7.75 (1H, m), 7.59- 7.54 (1H, m), 7.51-7.46 (1H, m), 3.92(3H, s), 3.06 (1H, br s).

TABLE 1-95 compound No. structural formula NMR 648

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, s), 7.63-7.59 (1H, m), 7.61 (1H, d, J =0.7 Hz), 7.40-7.37 (2H, m), 7.32- 7.22 (2H, m), 7.15 (1H, s), 7.10 (1H,d, J = 1.5 Hz), 4.96-4.92 (2H, m), 4.38- 4.32 (1H, m), 3.85-3.78 (4H,m), 2.58-2.48 (2H, m), 1.92-1.82 (1H, m), 0.92 (3H, d, J = 6.8 Hz), 0.90(3H, d, J = 6.6 Hz). 649

¹H-NMR (DMSO-D₆) δ: 8.28 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz),7.80 (1H, d, J = 7.9 Hz), 7.76- 7.74 (1H, m), 7.73-7.71 (1H, m), 7.66(1H, d, J = 7.3 Hz), 7.53-7.48 (1H, m), 7.39-7.35 (1H, m), 4.89 (1H, d,J = 13.5 Hz), 4.85 (1H, d, J = 13.7 Hz), 3.96 (2H, d, J = 7.1 Hz), 2.21-2.13 (1H, m), 0.88 (3H, d, J = 1.1 Hz), 0.86 (3H, d, J = 1.1 Hz). 650

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz),7.80 (1H, d, J = 7.7 Hz), 7.76 (1H, d, J = 1.8 Hz), 7.73 (1H, s), 7.66(1H, d, J = 7.5 Hz), 7.53-7.49 (1H, m), 7.39-7.34 (1H, m), 4.89 (1H, d,J = 13.7 Hz), 4.85 (1H, d, J = 14.1 Hz), 3.95 (3H, s), 0.94 (8H, s). 651

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.64-7.59 (2H, m), 7.63 (1H, s),7.39-7.35 (1H, m), 7.33-7.23 (3H, m), 7.21 (1H, s), 6.55-6.48 (1H, m),6.40 (1H, dq, J = 17.2, 5.3 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m),3.86-3.77 (4H, m), 1.88 (3H, dd, J = 6.5, 1.2 Hz). 652

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61(1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.39-7.36 (1H, m), 7.32-7.22(2H, m), 7.15 (1H, s), 7.13 (1H, d, J = 1.5 Hz), 4.96-4.93 (2H, m),4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 2.69-2.60 (2H, m), 1.70-1.57 (2H,m), 0.93 (3H, t, J = 7.4 Hz). 653

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, s), 7.64-7.59 (1H, m), 7.61 (1H, s),7.47-7.44 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22 (2H, m), 7.17 (1H, s),7.15 (1H, d, J = 1.2 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86-3.78 (4H, m), 2.69 (2H, q, J = 7.5 Hz), 1.23 (3H, t, J = 7.7 Hz).

TABLE 1-96 compound No. structural formula NMR 654

¹H-NMR (DMSO-D₆) δ 7.93 (1H, d, J = 0.7 Hz), 7.61 (1H, d, J = 0.7 Hz),7.60- 7.58 (1H, m), 7.49-7.46 (1H, m), 7.38-7.33 (1H, m), 7.31-7.21 (2H,m), 7.16 (2H, br s), 4.98-4.93 (2H, m), 4.37-4.31 (1H, m), 3.85-3.76(4H, m), 3.02-2.94 (1H, m), 1.26 (3H, d, J = 7.2 Hz), 1.25 (3H, d, J =7.2 Hz). 655

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, br s), 7.92 (1H, d, J = 7.7 Hz), 7.69 (1H,br s), 7.63 (1H, d, J = 7.2 Hz), 7.55 (1H, br s), 7.47- 7.42 (1H, m),7.38-7.34 (1H, m), 7.34 (1H, d, J = 1.6 Hz), 7.25 (1H, s), 3.34 (2H, t,J = 6.8 Hz), 3.28-3.20 (2H, m), 2.68-2.60 (2H, m), 2.23-2.17 (2H, m),1.94- 1.85 (2H, m), 1.85-1.75 (2H, m). 656

¹H-NMR (DMSO-D₆) δ: 7.77 (1H, d, J = 7.7 Hz), 7.64 (1H, d, J = 7.4 Hz),7.52- 7.47 (1H, m), 7.41 (1H, br s), 7.40 (1H, br s), 7.38-7.33 (1H, m),7.15 (1H, s), 5.41 (1H, t, J = 5.3 Hz), 4.87-4.78 (2H, m), 3.34 (2H, t,J = 6.7 Hz), 3.24 (2H, t, J = 7.2 Hz), 2.65-2.61 (2H, m), 2.23-2.18 (2H,m), 1.94-1.86 (2H, m), 1.83-1.74 (2H, m). 657 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, d, J = 0.7 Hz), 7.71- 7.65 (2H, m), 7.67(1H, d, J = 0.7 Hz), 7.48-7.31 (4H, m), 7.34 (1H, s), 4.97 (1H, t, J =5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.83 (2H, dt, J = 5.3, 5.6 Hz), 3.52-3.42 (4H, m), 1.93-1.80 (4H, m). 658

¹H-NMR (DMSO-D₆) δ: 9.24 (1H, s), 9.23 (2H, br s), 8.23 (1H, br s), 8.09(1H, br s), 8.03 (1H, d, J = 7.7 Hz), 7.97 (1H, d, J = 1.9 Hz), 7.86(1H, br s), 7.71 (1H, d, J = 7.4 Hz), 7.55- 7.50 (1H, m), 7.48-7.43 (1H,m), 7.45 (1H, s). 659 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.31 (1H, s), 8.14 (1H, br s), 7.99 (1H, d, J = 0.5Hz), 7.91 (1H, d, J = 7.4 Hz), 7.84 (1H, br s), 7.74 (1H, br s), 7.71(1H, d, J = 1.6 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.48-7.43 (1H, m),7.40-7.34 (1H, m), 7.31 (1H, s), 3.94 (2H, s), 0.93 (9H, s).

TABLE 1-97 compound No. structural formula NMR 660 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 8.25 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz),7.80 (1H, d, J = 7.9 Hz), 7.76 (1H, d, J = 1.6 Hz), 7.74- 7.72 (1H, m),7.66 (1H, d, J = 7.4 Hz), 7.54-7.48 (1H, m), 7.40-7.34 (1H, m), 7.22(1H, s), 5.46 (1H, br s), 4.92-4.83 (2H, m), 3.95 (2H, s), 0.94 (9H, s).661

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d,J = 7.7 Hz), 7.75 (1H, d, J = 1.4 Hz), 7.73-7.71 (1H, m), 7.66 (1H, d, J= 7.7 Hz), 7.54-7.48 (1H, m), 7.39- 7.34 (1H, m), 7.23 (1H, s), 5.47(1H, t, J = 5.4 Hz), 4.92-4.83 (2H, m), 4.76 (1H, s), 4.06 (2H, s), 1.10(3H, s), 1.10 (3H, s). 662

¹H-NMR (DMSO-D₆) δ: 8.33 (1H, s), 8.13 (1H, br s), 7.98 (1H, s), 7.92(1H, d, J = 7.7 Hz), 7.84 (1H, br s), 7.73 (1H, br s), 7.70 (1H, d, J =1.8 Hz), 7.65 (1H, d, J = 7.5 Hz), 7.49-7.44 (1H, m), 7.40- 7.35 (1H,m), 7.30 (1H, s), 3.98 (2H, d, J = 7.1 Hz), 1.92- 1.80 (1H, m),1.72-1.50 (5H, m), 1.26-1.10 (3H, m), 1.03-0.92 (2H, m). 663 (opticallyactive form)

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, s), 7.63-7.59 (1H, m), 7.60 (1H, d, J =0.7 Hz), 7.44-7.41 (1H, m), 7.33- 7.25 (3H, m), 7.16 (1H, s), 7.13-7.11(1H, m), 4.59 (2H, t, J = 4.9 Hz), 4.22 (2H, d, J = 7.1 Hz), 3.48- 3.40(4H, m), 2.39 (3H, s), 2.19-2.13 (1H, m). 664 (optically active form)

¹H-NMR (CDCl₃) δ: 7.72-7.68 (1H, m), 7.66-7.64 (1H, m), 7.59-7.55 (2H,m), 7.31- 7.21 (3H, m), 7.15-7.13 (1H, m), 6.32-6.29 (1H, m), 4.37-4.31(1H, m), 4.21- 4.10 (4H, m), 3.23-3.07 (1H, m), 2.90-2.71 (2H, m), 1.95(3H, d, J = 1.3 Hz), 1.93 (3H, d, J = 1.3 Hz). 665 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61(1H, d, J = 0.7 Hz), 7.41-7.37 (2H, m), 7.32-7.22 (2H, m), 7.15 (1H, s),7.10 (1H, d, J = 1.5 Hz), 4.97-4.92 (2H, m), 4.39-4.32 (1H, m),3.86-3.79 (4H, m), 2.58- 2.48 (2H, m), 1.92-1.82 (1H, m), 0.93 (3H, d, J= 6.6 Hz), 0.91 (6H, d, J = 6.6 Hz).

TABLE 1-98 compound No. structural formula NMR 666

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61(1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22(2H, m), 7.16 (1H, s), 7.14 (1H, d, J = 1.62 Hz), 4.98-4.94 (2H, m),4.38-4.32 (1H, m), 3.86-3.77 (4H, m), 2.65- 2.59 (2H, m), 1.53-1.47 (2H,m), 0.96 (9H, s). 667 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.33 (1H, d, J = 0.7 Hz), 8.13 (1H, br s), 7.98 (1H,d, J = 0.9 Hz), 7.92 (1H, d, J = 7.5 Hz), 7.84 (1H, br s), 7.73 (1H, brs), 7.70 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.3 Hz), 7.49-7.44 (1H,m), 7.40- 7.35 (1H, m), 7.30 (1H, s), 3.98 (2H, d, J = 7.3 Hz),1.92-1.80 (1H, m), 1.73-1.50 (5H, m), 1.26- 1.10 (3H, m), 1.03-0.91 (2H,m). 668 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.27 (1H, s), 7.92 (1H, s), 7.80 (1H, d, J = 7.9Hz), 7.74 (1H, s), 7.72 (1H, s), 7.66 (1H, d, J = 7.4 Hz), 7.53-7.48(1H, m), 7.40-7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.3 Hz),4.91-4.82 (2H, m), 3.98 (2H, d, J = 7.2 Hz), 1.91-1.79 (1H, m),1.72-1.50 (5H, m), 1.26- 1.11 (3H, m), 1.03-0.92 (2H, m). 669 (opticallyactive form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (1H, m), 7.61(1H, d, J = 0.7 Hz), 7.45-7.41 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22(2H, m), 7.16 (1H, s), 7.14 (1H, d, J = 1.6 Hz), 4.98-4.93 (2H, m),4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 2.65-2.59 (2H, m), 1.54-1.47 (2H,m), 0.96 (9H, s).

TABLE 1-99 compound No. structural formula NMR 670

¹H-NMR (DMSO-D₆) δ 12.17 (1H, br s), 7.97 (1H, s), 7.65-7.58 (2H, m),7.43 (1H, s), 7.32-7.22 (3H, m), 7.17 (1H, s), 7.13-7.12 (1H, m), 4.24(2H, t, J = 6.7 Hz), 2.38 (3H, s), 2.27 (2H, t, J = 7.4 Hz), 2.13- 2.04(2H, m). 671

¹H-NMR (DMSO-D₆) δ: 8.14- 8.10 (1H, m), 8.07-8.01 (3H, m), 7.73-7.69(1H, m), 7.63-7.57 (1H, m), 7.56- 7.49 (2H, m). 672 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, d, J = 0.4 Hz), 7.67- 7.63 (1H, m), 7.66(1H, d, J = 0.9 Hz), 7.42-7.38 (1H, m), 7.40 (1H, s), 7.36-7.32 (3H, m),7.18-7.14 (1H, m), 3.96 (3H, s). 673 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.7 Hz),7.65- 7.62 (1H, m), 7.44-7.42 (1H, m), 7.40-7.36 (2H, m), 7.35-7.26 (2H,m), 7.21- 7.17 (1H, m), 4.98-4.93 (2H, m), 3.84-3.79 (2H, m), 3.76-3.70(2H, m), 1.52 (3H, s). 674 (optically active form)

¹H-NMR (DMSO-D₆) δ 7.97 (1H, s), 7.67 (1H, s), 7.66-7.63 (1H, m), 7.44-7.38 (3H, m), 7.36-7.27 (2H, m), 7.21-7.17 (1H, m), 4.79 (1H, s), 4.13(2H, s), 1.15 (6H, s). 675 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.08 (1H, d, J = 0.5 Hz), 7.68 (1H, s), 7.66-7.62(1H, m), 7.41-7.36 (3H, m), 7.36- 7.28 (2H, m), 7.23-7.18 (1H, m), 5.08(1H, t, J = 5.6 Hz), 3.66 (2H, d, J = 5.6 Hz), 1.55 (6H, s).

TABLE 1-100 compound No. structural formula NMR 676 (optically activeform)

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.54-7.48 (2H, m), 7.32-7.21 (4H,m), 7.11- 7.09 (1H, m), 4.00 (3H, s), 2.80-2.74 (2H, m), 1.86- 1.80 (2H,m), 1.31 (6H, s). 677 (optically active form)

¹H-NMR (CDCl₃) δ: 7.71-7.67 (1H, m), 7.59-7.57 (2H, m), 7.54-7.52 (1H,m), 7.30- 7.23 (3H, m), 7.13-7.11 (1H, m), 4.37-4.32 (2H, m), 4.13-4.07(2H, m), 3.05 (1H, s), 3.00-2.95 (1H, m), 2.82-2.74 (2H, m), 1.87- 1.80(2H, m), 1.31 (7H, s). 678 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.57 (1H, m), 7.61 (1H, s),7.31-7.20 (3H, m), 7.22 (1H, s), 7.16-7.11 (1H, m), 6.82- 6.80 (1H, m),4.64 (1H, t, J = 5.4 Hz), 3.95 (3H, s), 3.77 (2H, s), 3.29 (2H, d, J =5.3 Hz), 0.94 (6H, s). 679 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.57 (1H, m), 7.33-7.30 (1H, m), 7.27-7.24 (2H, m), 7.22 (1H, s), 7.15-7.13 (1H, m), 6.83-6.81 (1H, m), 4.97 (1H, t, J = 5.3 Hz), 4.65 (1H, t, J = 5.4 Hz), 4.25(2H, t, J = 5.6 Hz), 3.85-3.80 (2H, m), 3.77 (2H, s), 3.29 (2H, d, J =5.3 Hz), 0.95 (6H, s). 680 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.59 (2H, m), 7.32-7.26 (3H, m),7.26- 7.24 (1H, m), 7.23 (1H, s), 6.91-6.89 (1H, m), 4.96 (1H, t, J =5.7 Hz), 3.95 (3H, s), 3.41 (2H, d, J = 5.6 Hz), 1.25 (3H, s), 1.24 (3H,s). 681 (optically active form)

¹H-NMR (CDCl₃) δ: 7.71-7.67 (1H, m), 7.58 (2H, s), 7.34-7.32 (1H, m),7.30- 7.22 (3H, m), 6.90-6.89 (1H, m), 4.36-4.33 (2H, m), 4.13-4.09 (2H,m), 3.65- 3.61 (2H, m), 3.14 (1H, s), 3.03-2.98 (1H, m), 2.18- 2.13 (1H,m), 1.36 (3H, s), 1.33 (3H, s).

TABLE 1-101 compound No. structural formula NMR 682 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.70- 7.65 (1H, m), 7.57-7.53 (1H, m), 7.53-7.48(3H, m), 7.46-7.38 (3H, m), 4.94- 4.89 (2H, m), 3.83-3.74 (4H, m),3.23-3.19 (1H, m). 683 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.96- 7.94 (1H, m), 7.64-7.59 (1H, m), 7.58 (1H, d,J = 0.9 Hz), 7.45-7.42 (1H, m), 7.32-7.27 (3H, m), 7.16 (1H, s),7.12-7.09 (1H, m), 4.53 (1H, t, J = 5.4 Hz), 3.95 (3H, s), 3.17 (2H, d,J = 5.5 Hz), 2.63-2.55 (2H, m), 1.53-1.44 (2H, m), 0.88 (6H, s). 684(optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.59 (1H, m), 7.61(1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m), 7.37-7.24 (3H, m), 7.16 (1H, s),7.13-7.10 (1H, m), 4.96 (1H, t, J = 5.2 Hz), 4.53 (1H, t, J = 5.4 Hz),4.25 (2H, t, J = 5.6 Hz), 3.85-3.79 (2H, m), 3.17 (2H, d, J = 5.3 Hz),2.63- 2.56 (2H, m), 1.54-1.45 (2H, m), 0.88 (6H, s). 685 (opticallyactive form)

¹H-NMR (DMSO-D₆) δ: 8.11- 8.05 (1H, m), 7.91-7.86 (1H, m), 7.83-7.78(1H, m), 7.75-7.70 (1H, m), 7.63 (1H, s), 7.51-7.45 (2H, m), 4.91-4.86(2H, m), 3.89- 3.75 (4H, m), 3.31-3.23 (1H, m). 686 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.64-7.58 (1H, m), 7.61 (1H, s),7.44-7.35 (2H, m), 7.33-7.22 (2H, m), 7.18-7.13 (2H, m), 4.96 (2H, t, J= 5.4 Hz), 3.85- 3.78 (2H, m), 3.77-3.70 (2H, m), 2.39 (3H, s), 1.52(3H, s).

TABLE 1-102 compound No. structural formula NMR 687 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 8.10 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz),7.66- 7.62 (1H, m), 7.47-7.44 (1H, m), 7.40-7.37 (2H, m), 7.36-7.28 (2H,m), 7.22- 7.18 (1H, m), 4.78 (1H, s), 1.63 (3H, s), 1.63 (3H, s), 1.08(3H, s), 1.07 (3H, s). 688 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.57 (1H, m), 7.61 (1H, s),7.30-7.24 (3H, m), 7.22 (1H, s), 7.17-7.14 (1H, m), 6.84- 6.80 (1H, m),4.66 (1H, br s), 3.95 (3H, s), 3.78 (2H, s), 1.22 (3H, s), 1.22 (3H, s).689 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz),7.61- 7.56 (1H, m), 7.34-7.30 (1H, m), 7.29-7.23 (2H, m), 7.21 (1H, s),7.17-7.13 (1H, m), 6.85-6.82 (1H, m), 4.96 (1H, t, J = 5.3 Hz), 4.65(1H, s), 4.25 (2H, t, J = 5.6 Hz), 3.84-3.80 (2H, m), 3.79 (2H, s), 1.22(3H, s), 1.22 (3H, s). 690 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64-7.59 (2H, m), 7.44-7.40 (1H, m),7.33- 7.21 (3H, m), 7.17 (1H, s), 7.15-7.10 (2H, m), 4.27 (2H, t, J =6.5 Hz), 3.02- 2.95 (2H, m), 2.92-2.89 (3H, m), 2.37 (3H, s), 2.10- 2.01(2H, m). 691 (optically active form)

¹H-NMR (DMSO-D₆) δ: 16.09 (1H, br s), 8.01 (1H, d, J = 0.7 Hz),7.65-7.60 (1H, m), 7.63 (1H, d, J = 0.7 Hz), 7.45-7.42 (1H, m),7.33-7.23 (3H, m), 7.20- 7.16 (1H, m), 7.15-7.11 (1H, m), 4.32 (2H, t, J= 6.6 Hz), 2.93 (2H, t, J = 7.7 Hz), 2.39 (3H, s), 2.36-2.27 (2H, m).

TABLE 1-103 compound No. structural formula NMR 692 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 8.13-8.10 (1H, m), 7.77-7.73(1H, m), 7.67-7.63 (1H,m), 7.44-7.40 (2H, m), 7.38-7.28 (3H, m), 7.18-7.14 (1H, m), 6.83-6.78(1H, m), 4.61-4.48 (2H, m), 4.42-4.31 (1H, m). 693 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.72 (1H, s), 7.66-7.62 (1H, m), 7.46-7.38 (3H, m), 7.36-7.27 (3H, m), 7.25-7.20 (1H, m), 7.02 (1H, br s),1.80 (3H, s), 1.79 (3H, s). 694 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.16 (1H, d, J = 0.7 Hz), 7.73 (1H, d, J = 0.4 Hz),7.66-7.63 (1H, m), 7.52-7.47 (1H, m), 7.43-7.38 (3H, m), 7.36- 7.29 (2H,m), 7.24-7.20 (1H, m), 2.63 (3H, d, J = 4.6 Hz), 1.79 (3H, s), 1.79 (3H,s). 695 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.23 (1H, s), 7.80 (1H, s), 7.68-7.63 (1H, m), 7.44-7.40 (2H, m), 7.37-7.31 (3H, m), 7.25-7.21 (1H, m), 3.00-2.20 (6H, m),1.77 (3H, s), 1.77 (3H, s). 696 (optically active form)

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.54 (1H, s), 7.51-7.49 (2H, m),7.28- 7.19 (3H, m), 7.10-7.07 (1H, m), 4.34-4.29 (2H, m), 4.31 (3H, s),3.20 (1H, s), 2.94 (2H, t, J = 7.2 Hz), 2.46-2.38 (2H, m), 2.42 (3H, s).

TABLE 1-104 compound No. structural formula NMR 697 (optically activeform)

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.63 (1H, s), 7.55 (1H, s),7.51-7.49 (1H, m), 7.31-7.20 (3H, m), 7.09-7.08 (1H, m), 4.40 (2H, t, J= 6.4 Hz), 4.01 (3H, s), 2.93 (2H, t, J = 7.1 Hz), 2.78 (1H, s),2.58-2.51 (2H, m), 2.43 (3H, s). 698 (optically active form)

¹H-NMR (CDCl₃) δ: 7.72-7.67 (1H, m), 7.56-7.52 (1H, m ), 7.48 (1H, s),7.45 (1H, s), 7.33-7.21 (3H, m), 7.11 (1H, s), 3.99 (3H, s), 3.38 (1H,s), 2.84 (1H, d, J = 13.0 Hz), 2.80 (1H, d, J = 13.2 Hz), 1.43 (1H, brs), 1.28 (3H, s), 1.25 (3H, s). 699 (optically active form)

¹H-NMR (CDCl₃) δ: 7.71-7.67 (1H, m), 7.56 (1H, s), 7.53 (1H, s),7.47-7.44 (1H, m), 7.31-7.20 (3H, m), 7.04- 7.02 (1H, m), 4.35-4.31 (2H,m), 4.11-4.07 (2H, m), 3.10 (1H, br s), 2.96-2.91 (1H, m), 2.56 (2H, s),0.95 (9H, s). 700 (optically active form)

¹H-NMR (CDCl₃) δ: 7.94-7.92 (1H, m), 7.77-7.72 (1H, m), 7.64 (1H, s),7.63 (1H, s), 7.59-7.57 (1H, m), 7.44- 7.30 (3H, m), 4.40-4.34 (2H, m),4.15-4.08 (2H, m), 3.19 (1H, br s), 2.83 (1H, t, J = 5.8 Hz). 701(optically active form)

¹NMR (CDCl₃) δ: 8.24-8.22 (1H, m), 7.89-7.86 (1H, m), 7.77-7.73 (1H, m),7.63 (2H, s), 7.41-7.36 (2H, m), 7.32-7.27 (1H, m), 4.38- 4.35 (2H, m),4.14-4.09 (2H, m), 3.23 (1H, br s), 2.94 (1H, t, J = 5.9 Hz), 2.65 (3H,s).

TABLE 1-105 compound No. structural formula NMR 702 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 0.7 Hz), 7.65-7.58 (2H, m), 7.62(1H, d, J = 0.7 Hz), 7.42-7.24 (5H,m), 7.19 (1H, s), 4.98-4.92 (2H, m),3.84-3.79 (2H, m), 3.77-3.70 (2H, m), 1.52 (3H, s). 703 (opticallyactive form)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J = 0.7 Hz), 7.70 (1H, d, J = 0.7 Hz),7.65- 7.61 (1H, m), 7.51-7.47 (1H, m), 7.40-7.36 (2H, m), 7.35-7.30 (1H,m), 7.29- 7.24 (1H, m), 7.21-7.17 (1H, m), 4.83 (3H, t, J = 5.4 Hz),3.90 (6H, d, J = 5.6 Hz). 704 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, d, J = 0.7 Hz), 7.69 (1H, d, J = 0.7 Hz),7.66-7.62 (1H, m), 7.42-7.37 (2H, m), 7.38 (1H, s), 7.36-7.31 (1H, m),7.29-7.25 (1H, m), 7.21-7.16 (1H, m), 4.90-4.86 (2H, m), 3.91-3.81 (4H,m), 1.92 (2H, q, J = 7.4 Hz), 0.75 (3H, t, J = 7.5 Hz). 705 (opticallyactive form)

¹H-NMR (DMSO-D₆) δ: 8.01 (1H, s), 7.68 (1H, s), 7.66-7.61 (1H, m), 7.45-7.37 (2H, m), 7.36-7.27 (3H, m), 7.20-7.15 (1H, m), 4.66-4.52 (3H, m),3.42- 3.29 (2H, m), 3.27-3.15 (2H, m), 2.13-2.01 (2H, m), 1.99-1.86 (2H,m). 706 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 0.7 Hz), 7.65- 7.59 (2H, m), 7.64(1H, s), 7.49-7.46 (1H, m), 7.41- 7.36 (1H, m), 7.35-7.30 (2H, m),7.28-7.23 (1H, m), 7.19 (1H, s), 4.82 (3H, t, J = 5.4 Hz), 3.92 (6H, d,J = 5.5 Hz).

TABLE 2-1 compound No. structural formula NMR 707 (optically activeform)

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 0.7 Hz), 7.63- 7.59 (1H, m), 7.62(1H, d, J = 0.7 Hz), 7.46-7.40 (2H, m), 7.31-7.21 (2H, m), 7.14 (2H, s),4.82 (3H, t, J = 5.6 Hz), 3.91 (6H, d, J = 5.6 Hz), 2.39 (3H, s).

Among these compounds, compound Nos. 42-44, 56, 57, 72, 73 and 143 areReference Examples.

Among the above-mentioned optically active compounds, the structuralformulas of the compounds having a specified absolute configuration areshown in the following Table 2-1 to 2-11.

TABLE 2-1 compound structural formula No. (absolute configuration) 520

526

529

531

532

TABLE 2-2 compound structural formula No. (absolute configuration) 533

534

537

538

539

TABLE 2-3 compound structural formula No. (absolute configuration) 543

544

545

546

548

TABLE 2-4 compound structural formula No. (absolute configuration) 549

550

551

565

566

TABLE 2-5 compound structural formula No. (absolute configuration) 574

575

576

595

605

TABLE 2-6 compound structural formula No. (absolute configuration) 606

607

610

663

TABLE 2-7 compound structural formula No. (absolute configuration) 670

672

673

674

675

TABLE 2-8 compound structural formula No. (absolute configuration) 682

685

686

687

690

TABLE 2-9 compound structural formula No. (absolute configuration) 691

692

693

694

TABLE 2-10 compound structural formula No. (absolute configuration) 695

696

697

702

TABLE 2-11 compound structural formula No. (absolute configuration) 703

704

705

706

707

The Formulation Examples of the present invention include the followingpreparations, which are not to be construed as limitative.

Formulation Example 1 Production of Capsule

1) compound of Example 1 30 mg 2) microcrystalline cellulose 10 mg 3)lactose 19 mg 4) magnesium stearate  1 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 Production of Tablet

1) compound of Example 1 10 g 2) lactose 50 g 3) cornstarch 15 g 4)carmellose calcium 44 g 5) magnesium stearate  1 g

The total amount of 1), 2) and 3), and 30 g of 4) are kneaded withwater, dried in vacuo and sieved. The sieved powder is mixed with 14 gof 4) and 1 g of 5) and the mixture is tableted by a tableting machine,whereby 1000 tablets containing 10 mg of the compound of Example 1 pertablet are obtained.

Experimental Example 1 Inhibitory Action of PDHK Activity in Vitro

The inhibitory action of PDHK activity was indirectly evaluated byperforming a kinase reaction in the presence of a test compound andmeasuring the residual PDH activity.

In the case of human PDHK2 (hPDHK2, Genbank Accession No. NM_(—)002611),modified hPDHK2 cDNA wherein FLAG-Tag sequence is added to the Nterminal by a polymerase linkage reaction was prepared based on hPDHK2cDNA clone (pReceiver-M01/PDK2-GeneCopoeia), and cloned into a vector(pET17b-Novagen). The recombinant construct was transformed intoEscherichia coli (DH5α-TOYOBO). The recombinant clones were identified,plasmid DNA was isolated and subjected to the DNA sequence analysis. Oneclone which had the expected nucleic acid sequence was selected forexpression work.

For expression of hPDHK2 activity, Escherichia coli strain BL21(DE3)cells (Novagen) were transformed with the pET17b vector containingmodified hPDHK2 cDNA. Escherichia coli were grown to an optical density0.6 (600 nmol/L) at 30° C. Protein expression was induced by theaddition of 500 μmol/L isopropyl-β-thiogalactopyranoside. Escherichiacoli were cultured at 30° C. for 5 hr and harvested by centrifugation.Resuspension of the Escherichia coli paste was disrupted by amicrofluidizer. FLAG-Tagged protein was separated using FLAG affinitygel (Sigma). The gel was washed with 20 mmol/LN-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid-sodium hydroxide(HEPES-NaOH), 500 mmol/L sodium chloride, 1% ethylene glycol, and 0.1%Pluronic F-68 (pH 8.0), and the binding protein was eluted with 20mmol/L HEPES-NaOH, 100 μg/mL FLAG peptide, 500 mmol/L sodium chloride,1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0). The elutedfractions containing FLAG-Tagged protein were pooled, dialyzed against20 mmol/L HEPES-NaOH, 150 mmol/L sodium chloride, 0.5 mmol/Lethylenediaminetetraacetic acid (EDTA), 1% ethylene glycol, and 0.1%Pluronic F-68 (pH 8.0), and preserved at −80° C. During the assay, thehPDHK2 enzyme concentration was set to the minimal concentration atwhich PDH is inhibited the most.

0.05 U/mL PDH (porcine heart PDH complex, Sigma P7032) and 1.6 μg/mLhPDHK2 were mixed in a buffer (50 mmol/L 3-morpholinopropanesulfonicacid (pH 7.0), 20 mmol/L dipotassium hydrogen phosphate, 60 mmol/Lpotassium chloride, 2 mmol/L magnesium chloride, 0.4 mmol/L EDTA, and0.2% Pluronic F-68, 2 mmol/L dithiothreitol), the mixture was incubatedat 4° C. overnight to give PDH/hPDHK2 complex. The test compound wasdiluted with dimethyl sulfoxide (DMSO). PDH/hPDHK2 complex (20 μL), testcompound (1.5 μL) and 3.53 μmol/L ATP (diluted with buffer, 8.5 μL) wereadded to a half area 96 well UV-transparent microplate (Corning 3679),and PDHK reaction was performed at room temperature for 45 min. Insteadof the test compound, DMSO (1.5 μL) was added to a control well. DMSO(1.5 μL) was added instead of the test compound to a blank well for themeasurement of the maximum rate of PDH reaction, and hPDHK2 was notadded. Than, 10 μL of substrates (5 mmol/L sodium pyruvate, 5 mmol/LCoenzyme A, 12 mmol/L NAD, and 5 mmol/L thiamine pyrophosphate, dilutedwith buffer) was added. The mixture was incubated at room temperaturefor 90 min, and the residual PDH activity was measured. The absorbanceat 340 nm before and after PDH reaction was measured on a microplatereader to detect NADH produced by the PDH reaction. The PDHK inhibitoryrate (%) of the test compound was calculated from the formula [{(PDHactivity of test compound−PDH activity of control)/PDH activity ofblank−PDH activity of control)}×100]. The IC₅₀ value was calculated fromthe concentrations of the test compound at two points enclosing 50%inhibition of the PDHK activity.

The obtained results are shown in the following Table 3-1-Table 3-29. Inthe Tables, the inhibitory activity of the compound is shown as follows.+++: IC₅₀ (μmol/L) of less than 0.1 μmol/L, ++: not less than 0.1 μmol/Land less than 1 μmol/L, +: not less than 1 μmol/L. The compounds forwhich the measurement was not conducted is shown as ND.

TABLE 3-1 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 1 + 2.2082 + 2.286 3 + 1.567 4 + 2.292 5 + 1.169 6 + 2.294 7 + 1.435 8 + 45.6439 + 20.040 10 + 30.793 11 + 6.792 12 + 5.495 13 + 15.876 14 + 56.57415 + 16.312 16 + 19.303 17 + 13.871 18 ++ 0.457 19 + >100 20 + 3.497 21++ 0.302 22 + 16.691 23 ++ 0.571 24 + >100 25 + 30.863

TABLE 3-2 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 26 +17.596 27 ++ 0.848 28 + 2.815 29 + 5.739 30 + 8.609 31 + 1.353 32 + >10033 + 1.814 34 + 33.181 35 + >100 36 ++ 0.626 37 + 3.959 38 + 12.022 39 +4.522 40 + 2.469 41 + 68.593 42 + 5.564 43 + 3.920 44 + >100 45 ++ 0.24746 + 6.486 47 + 4.909 48 ++ 0.639 49 + 1.787 50 ++ 0.100

TABLE 3-3 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 51 + 2.59052 + 4.010 53 ++ 0.567 54 + 21.913 55 + 19.786 56 + >100 57 + 5.621 58++ 0.195 59 ++ 0.772 60 + 2.037 61 ++ 0.294 62 + 15.728 63 + 8.484 64 +17.963 65 + >100 66 + 66.305 67 + 4.199 68 ++ 0.624 69 + 16.015 70 +2.213 71 + 10.220 72 + 4.424 73 + 4.814 74 + 3.317 75 + 6.783

TABLE 3-4 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 76 + 1.75477 + 2.497 78 + 1.358 79 ++ 0.696 80 + 8.245 81 + 2.762 82 + 67.348 83 +1.141 84 + 42.066 85 + 23.099 86 ++ 0.378 87 ++ 0.669 88 + 2.526 89 +2.147 90 ++ 0.474 91 +++ 0.072 92 ++ 0.405 93 + 29.507 94 +++ 0.049 95 +7.831 96 + 6.568 97 ++ 0.849 98 + 2.423 99 ++ 0.718 100 + 6.148

TABLE 3-5 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 101 +10.296 102 ++ 0.323 103 ++ 0.151 104 ++ 0.279 105 ++ 0.259 106 ++ 0.461107 + 2.613 108 ++ 0.462 109 + 1.317 110 + 2.488 111 + >10 112 + 1.230113 + 1.113 114 +++ 0.051 115 ++ 0.417 116 ++ 0.601 117 ++ 0.909 118 ++0.839 119 + 1.005 120 ++ 0.174 121 + 3.676 122 +++ 0.049 123 ++ 0.877124 ++ 0.736 125 ++ 0.227

TABLE 3-6 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 126 + >10127 + >10 128 + 2.395 129 ++ 0.864 130 + >10 131 + >10 132 ++ 0.694133 + 2.498 134 + >10 135 + >1 136 +++ 0.025 137 + 1.007 138 + >10139 + >10 140 + 2.402 141 +++ 0.077 142 ++ 0.543 143 + >10 144 + 1.122145 + 1.382 146 ++ 0.213 147 + 1.729 148 + 8.450 149 + 1.220 150 + 6.838

TABLE 3-7 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 151 +5.213 152 +++ 0.054 153 +++ 0.036 154 ++ 0.309 155 ++ 0.805 156 ++ 0.464157 ++ 0.358 158 ++ 0.221 159 ++ 0.318 160 + 2.538 161 + 2.113 162 +2.886 163 ++ 0.232 164 + 2.747 165 ++ 0.957 166 + 5.899 167 + 1.947168 + >10 169 + 7.362 170 + 6.735 171 ++ 0.951 172 ++ 0.779 173 + >10174 +++ 0.066 175 ++ 0.517

TABLE 3-8 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 176 +8.013 177 + 9.189 178 + >10 179 + 1.340 180 + >10 181 + 1.514 182 + >10183 + >10 184 + >10 185 +++ 0.053 186 + 5.906 187 + 2.478 188 ++ 0.383189 + 6.000 190 + >10 191 ++ 0.216 192 ++ 0.182 193 ++ 0.560 194 ++0.368 195 + 5.485 196 ++ 0.475 197 ++ 0.298 198 ++ 0.126 199 ++ 0.182200 ++ 0.236

TABLE 3-9 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 201 ++0.162 202 ++ 0.247 203 ++ 0.423 204 + >10 205 ++ 0.707 206 + 2.240 207++ 0.998 208 ++ 0.677 209 ++ 0.281 210 + 1.327 211 + 1.012 212 ++ 0.685213 ++ 0.173 214 ++ 0.345 215 + 4.599 216 + 2.565 217 + 5.329 218 +1.837 219 + >10 220 ++ 0.488 221 + >10 222 + 5.391 223 + 2.327 224 ++0.214 225 ++ 0.619

TABLE 3-10 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 226 +1.142 227 + 1.048 228 + 2.192 229 ++ 0.552 230 + 3.712 231 + 3.607 232 +1.988 233 ++ 0.142 234 +++ 0.058 235 ++ 0.803 236 ++ 0.355 237 + 1.999238 ++ 0.252 239 ++ 0.178 240 ++ 0.149 241 +++ 0.098 242 +++ 0.086 243+++ 0.075 244 + 2.929 245 ++ 0.190 246 ++ 0.809 247 ++ 0.547 248 + 1.019249 ++ 0.719 250 + 1.609

TABLE 3-11 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 251 + >10252 + 1.273 253 + 1.947 254 + 1.131 255 + 1.078 256 + 1.003 257 ++ 0.567258 + 2.625 259 + 1.386 260 + 2.813 261 + 1.404 262 + 1.365 263 ++ 0.133264 + 1.169 265 + 1.258 266 + 1.556 267 + 1.197 268 + >10 269 + 1.338270 ++ 0.533 271 +++ 0.056 272 ++ 0.342 273 ++ 0.396 274 + 7.487 275 ++0.278

TABLE 3-12 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 276 +1.013 277 ++ 0.125 278 ++ 0.862 279 + 1.849 280 + 1.514 281 + 1.000 282++ 0.226 283 ++ 0.571 284 + 1.168 285 +++ 0.020 286 +++ 0.017 287 + >10288 ++ 0.635 289 ++ 0.641 290 ++ 0.793 291 + 5.826 292 + 2.571 293 +4.947 294 ++ 0.710 295 ++ 0.861 296 ++ 0.180 297 + 3.034 298 ++ 0.177299 ++ 0.235 300 ++ 0.114

TABLE 3-13 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 301 +1.586 302 + 1.167 303 ++ 0.755 304 ++ 0.723 305 ++ 0.562 306 ++ 0.453307 + 3.198 308 + 2.666 309 + >10 310 + >10 311 + 7.151 312 + 1.824313 + >10 314 + >10 315 + 6.371 316 + 4.480 317 + 2.313 318 ++ 0.553319 + 3.086 320 + 8.765 321 + 5.385 322 + 2.503 323 ++ 0.362 324 ++0.203 325 + 1.080

TABLE 3-14 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 326 ++0.303 327 + 2.941 328 +++ 0.078 329 +++ 0.066 330 ++ 0.125 331 + 1.415332 ++ 0.912 333 ++ 0.924 334 ++ 0.674 335 +++ 0.080 336 + >10 337 ++0.499 338 + >1 339 ++ 0.177 340 + 1.594 341 +++ 0.079 342 +++ 0.047 343+++ 0.053 344 + >1 345 ++ 0.121 346 ++ 0.200 347 +++ 0.088 348 ++ 0.634349 ++ 0.126 350 ++ 0.152

TABLE 3-15 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 351 ++0.168 352 ++ 0.109 353 + 7.398 354 +++ 0.071 355 +++ 0.040 356 +++ 0.053357 + 1.939 358 +++ 0.034 359 ++ 0.187 360 ++ 0.548 361 ++ 0.436 362 +1.077 363 +++ 0.047 364 ++ 0.178 365 + 1.327 366 + 2.170 367 + >1 368 ++0.180 369 +++ 0.081 370 ++ 0.114 371 ++ 0.617 372 ++ 0.564 373 +++ 0.049374 +++ 0.049 375 +++ 0.050

TABLE 3-16 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 376 +++0.085 377 ++ 0.189 378 ++ 0.703 379 ++ 0.351 380 + 1.490 381 ++ 0.495382 ++ 0.863 383 + 1.225 384 ++ 0.219 385 ++ 0.234 386 +++ 0.089 387 +++0.063 388 +++ 0.063 389 ++ 0.822 390 ++ 0.954 391 ++ 0.485 392 ++ 0.200393 ++ 0.176 394 +++ 0.058 395 ++ 0.699 396 ++ 0.627 397 ++ 0.424 398 ++0.119 399 ++ 0.149 400 + 7.077

TABLE 3-17 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 401 ++0.554 402 + >10 403 + >10 404 ++ 0.195 405 + 6.377 406 +++ 0.025 407 +++0.031 408 +++ 0.065 409 +++ 0.067 410 ++ 0.154 411 +++ 0.066 412 +++0.022 413 + 1.230 414 +++ 0.032 415 + 9.190 416 ++ 0.104 417 + >1 418 +6.065 419 ++ 0.504 420 ++ 0.225 421 ++ 0.233 422 +++ 0.023 423 +++ 0.021424 +++ 0.023 425 +++ 0.021

TABLE 3-18 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 426 +++0.024 427 +++ 0.020 428 +++ 0.025 429 +++ 0.019 430 +++ 0.064 431 ++0.250 432 ++ 0.247 433 ++ 0.388 434 ++ 0.561 435 +++ 0.039 436 +++ 0.065437 +++ 0.060 438 ++ 0.112 439 +++ 0.034 440 +++ 0.032 441 +++ 0.036 442+++ 0.040 443 + 1.152 444 + 3.934 445 ++ 0.605 446 ++ 0.565 447 ++ 0.202448 ++ 0.381 449 +++ 0.047 450 ++ 0.442

TABLE 3-19 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 451 ++0.102 452 + 2.719 453 +++ 0.028 454 +++ 0.064 455 +++ 0.026 456 +++0.045 457 +++ 0.030 458 +++ 0.039 459 ++ 0.185 460 +++ 0.030 461 +++0.030 462 + 5.979 463 +++ 0.047 464 +++ 0.042 465 +++ 0.061 466 +++0.055 467 +++ 0.018 468 ++ 0.327 469 ++ 0.193 470 ++ 0.168 471 +++ 0.026472 ++ 0.184 473 +++ 0.090 474 +++ 0.019 475 +++ 0.020

TABLE 3-20 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 476 +++0.053 477 +++ 0.018 478 ++ 0.433 479 + >10 480 ++ 0.553 481 ++ 0.251 482+++ 0.040 483 ++ 0.542 484 +++ 0.024 485 ++ 0.117 486 +++ 0.055 487 +++0.064 488 +++ 0.052 489 +++ 0.022 490 ++ 0.223 491 +++ 0.020 492 +++0.040 493 +++ 0.039 494 +++ 0.044 495 ++ 0.119 496 +++ 0.023 497 +++0.031 498 +++ 0.047 499 +++ 0.039 500 +++ 0.031

TABLE 3-21 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 501 +++0.032 502 +++ 0.048 503 +++ 0.045 504 +++ 0.019 505 +++ 0.046 506 +++0.030 507 +++ 0.026 508 +++ 0.048 509 +++ 0.051 510 +++ 0.062 511 +++0.056 512 +++ 0.038 513 +++ 0.032 514 +++ 0.058 515 +++ 0.038 516 ++0.110 517 +++ 0.057 518 +++ 0.054 519 ++ 0.418 520 + 3.330 521 +++ 0.036522 +++ 0.061 523 +++ 0.048 524 +++ 0.087 525 ++ 0.677

TABLE 3-22 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 526 ++0.397 527 +++ 0.079 528 +++ 0.049 529 +++ 0.017 530 +++ 0.043 531 +++0.020 532 +++ 0.016 533 +++ 0.015 534 +++ 0.016 535 ++ 0.197 536 +++0.054 537 +++ 0.035 538 +++ 0.026 539 +++ 0.027 540 +++ 0.016 541 +++0.015 542 +++ 0.015 543 +++ 0.036 544 +++ 0.022 545 +++ 0.017 546 +++0.015 547 +++ 0.062 548 +++ 0.016 549 +++ 0.027 550 +++ 0.069

TABLE 3-23 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 551 ++0.109 552 +++ 0.017 553 +++ 0.018 554 +++ 0.020 555 + >1 556 +++ 0.053557 +++ 0.077 558 +++ 0.081 559 + >1 560 ++ 0.970 561 +++ 0.050 562 +++0.059 563 +++ 0.063 564 ++ 0.105 565 +++ 0.018 566 +++ 0.021 567 + >1568 +++ 0.083 569 +++ 0.044 570 ++ 0.110 571 +++ 0.050 572 ++ 0.109 573+++ 0.018 574 +++ 0.052 575 +++ 0.036

TABLE 3-24 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 576 +++0.030 577 +++ 0.023 578 +++ 0.078 579 +++ 0.019 580 +++ 0.021 581 +++0.019 582 +++ 0.021 583 +++ 0.064 584 +++ 0.077 585 +++ 0.026 586 ++0.513 587 +++ 0.021 588 +++ 0.029 589 +++ 0.025 590 + 5.922 591 + >1592 + >1 593 + >1 594 +++ 0.048 595 +++ 0.022 596 +++ 0.041 597 + >1 598++ 0.653 599 +++ 0.033 600 + >1

TABLE 3-25 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 601 + >1602 + >1 603 ++ 0.228 604 +++ 0.035 605 +++ 0.019 606 +++ 0.028 607 +++0.045 608 + >1 609 + >1 610 +++ 0.041 611 ++ 0.329 612 +++ 0.047 613 +++0.076 614 +++ 0.037 615 ++ 0.105 616 ++ 0.192 617 +++ 0.084 618 +++0.056 619 +++ 0.033 620 +++ 0.065 621 +++ 0.065 622 +++ 0.033 623 ++0.133 624 +++ 0.014 625 + >1

TABLE 3-26 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 626 ++0.674 627 + >1 628 +++ 0.058 629 +++ 0.045 630 +++ 0.020 631 +++ 0.062632 ++ 0.195 633 ++ 0.560 634 ++ 0.100 635 ++ 0.515 636 ++ 0.239637 + >1 638 ++ 0.127 639 +++ 0.063 640 ++ 0.732 641 ++ 0.510 642 + >1643 ++ 0.184 644 ++ 0.130 645 +++ 0.037 646 +++ 0.040 647 ++ 0.169 648+++ 0.044 649 +++ 0.037 650 +++ 0.036

TABLE 3-27 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 651 +++0.025 652 +++ 0.036 653 +++ 0.037 654 +++ 0.055 655 +++ 0.073 656 ++0.172 657 +++ 0.020 658 +++ 0.071 659 +++ 0.016 660 +++ 0.017 661 +++0.059 662 +++ 0.034 663 +++ 0.018 664 +++ 0.015 665 +++ 0.023 666 +++0.027 667 +++ 0.015 668 +++ 0.017 669 +++ 0.017 670 ND ND 671 + 1.443672 ND ND 673 +++ 0.022 674 +++ 0.030 675 ND ND

TABLE 3-28 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 676 ND ND677 ND ND 678 ND ND 679 ND ND 680 ND ND 681 ND ND 682 +++ 0.079 683 NDND 684 ND ND 685 ++ 0.338 686 ND ND 687 +++ 0.051 688 ND ND 689 ND ND690 ND ND 691 +++ 0.030 692 ND ND 693 ND ND 694 ND ND 695 ND ND 696 NDND 697 ND ND 698 ND ND 699 ND ND 700 ND ND

TABLE 3-29 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 701 ND ND702 +++ 0.030 703 +++ 0.020 704 ND ND 705 ND ND 706 +++ 0.031 707 +++0.019

As is clear from the above-mentioned Experimental Example 1, thecompound of the present invention has a PDHK activity inhibitory action.

Therefrom it is suggested that the compound of the present inventionprovides an effect of strong inhibition of PDHK.

Therefore, by inhibition of PDHK, the compound of the present inventioneffectively activates pyruvate dehydrogenase (PDH), and can provide anagent for the treatment or prophylaxis of diabetes (e.g., type 1diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolicsyndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrialdisease, mitochondrial encephalomyopathy or cancer and the like.Moreover, the compound of the present invention can provide an agent forthe treatment or prophylaxis of diabetic complications (e.g.,neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia,cerebral apoplexy or pulmonary hypertension.

INDUSTRIAL APPLICABILITY

The present invention is useful for the treatment or prophylaxis and thelike of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulinresistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia,atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia,hyperlactacidemia, mitochondrial disease, mitochondrialencephalomyopathy or cancer and the like. In addition, the presentinvention is useful for the treatment or prophylaxis and the like ofdiabetic complications (e.g., neuropathy, retinopathy, nephropathy,cataract etc.), brain ischemia, cerebral apoplexy or pulmonaryhypertension.

1. A compound represented by the following formula or a pharmaceuticallyacceptable salt thereof, or a solvate thereof:

wherein, R^(a) is (1) a hydrogen atom, or (2) a halogen atom; R^(b) is(1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the following group A, (4) a C₂₋₆ alkenyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group C, (5) a C₂₋₆ alkynyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup C, (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group B,(8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkylgroup optionally substituted by the same or different 1 to 5substituents selected from the following group B, (9)—C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or differentand each is a hydrogen atom or a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup B, (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are thesame or different and each is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the following group B, (11) —OR^(b7) wherein R^(b7) is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group B,(12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or differentand each is a hydrogen atom or a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup B, (13) —NR^(b10)—C(═O)—R_(b11) wherein R^(b10) and R^(b11) arethe same or different and each is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the following group B, (14) —NR^(b12)—C(═O)—OR^(b13)wherein R^(b12) is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group, and R^(b13) is a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group B, (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) andR^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group B, or (16) a grouprepresented by the following formula:

wherein Y^(b) is (i) a single bond, (ii) a C₁₋₆ alkylene, (iii) a C₂₋₆alkenylene, (iv) —O—(CH₂)_(n1)— wherein n1 is an integer of 0, or 1 to4, (v) —O—(CH₂)_(n2)—C(═O)— wherein n2 is an integer of 0, or 1 to 4,(vi) —C(═O)—, or (vii) —NR^(b16)— wherein R^(b16) is a hydrogen atom ora C₁₋₆ alkyl group optionally substituted by the same or different 1 to5 substituents selected from the following group B; ring T is (i) aC₆₋₁₀ aryl group, (ii) a C₃₋₁₀ cycloalkyl group, (iii) a C₅₋₁₀ bridgedcycloalkyl group, (iv) a monocyclic aromatic heterocyclic group whichcontains, besides carbon atom, 1 to 4 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7ring-constituting atoms, or (v) a monocyclic non-aromatic heterocyclicgroup which contains, besides carbon atom, 1 to 4 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7ring-constituting atoms, R^(j) are the same or different and each is asubstituent selected from the following group D, and p is an integer of0, or 1 to 4; R^(c) is (1) a hydrogen atom, (2) a halogen atom, (3) aC₁₋₆ alkyl group, (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atomor a C₁₋₆ alkyl group, (5) —OR^(c2) wherein R^(c2) is a hydrogen atom ora C₁₋₆ alkyl group, (6) —NR_(c3)R^(c4) wherein R^(c3) and R^(c4) are thesame or different and each is a hydrogen atom or a C₁₋₆ alkyl group, or(7) —NR_(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same ordifferent and each is a hydrogen atom or a C₁₋₆ alkyl group; X^(d) is anitrogen atom; R^(e) are the same or different and each is, (1) ahalogen atom, or (2) a C₁₋₆ alkyl group optionally substituted by thesame or different 1 to 5 substituents selected from the following groupC; and n is an integer of 0, or 1 to 3, Group A is selected from thegroup consisting of (a) a halogen atom, (b) a cyano group, (c)—C(═O)—R^(A1) wherein R^(A1) is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the following group B, (d) —C(═O)—OR^(A2) wherein R^(A2)is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by thesame or different 1 to 5 substituents selected from the following groupB, (e) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same ordifferent and each is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group B, (f) —C(═O)—NR^(A5)—OR^(A6) wherein R^(A5) andR^(A6) are the same or different and each is a hydrogen atom or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group B, (g) —OR^(A7) whereinR^(A7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup B, (h) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same ordifferent and each is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group B, (i) —NR^(A10)—C(═O)—R^(A11) wherein R^(A10) andR^(A11) are the same or different and each is a hydrogen atom or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group B, (j)—NR^(A12)—C(O)—OR^(A13) wherein R^(A12) is a hydrogen atom or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group B, and R^(A13) is a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group B, (k) —S(═O)₂—R^(A14)wherein R^(A14) is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group B, (l) —S(═O)₂—OR^(A15) wherein R^(A15) is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group B,and (m) —Si—(CH₂—CH₃)₃, Group B is selected from the group consisting of(a) a halogen atom, (b) a cyano group, (c) —C(═O)—R^(B1) wherein R^(B1)is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by thesame or different 1 to 5 substituents selected from the following groupC, (d) —C(═O)—OR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₆ alkylgroup optionally substituted by the same or different 1 to 5substituents selected from the following group C, (e)—C(═O)—NR^(B3)R^(B4) wherein R^(B3) and R^(B4) are the same or differentand each is a hydrogen atom or a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup C, (f) —C(═O)—NR^(B5)—OR^(B6) wherein R^(B5) and R^(B6) are thesame or different and each is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the following group C, (g) —OR^(B7) wherein R^(B7) is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group C,(h) —NR^(B8)R^(B9) wherein R^(B8) and R^(B9) are the same or differentand each is a hydrogen atom or a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup C, (i) —NR^(B10)—C(═O)—R^(B11) wherein R^(B10) and R^(B11) are thesame or different and each is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the following group C, (j) —NR^(B12)—S(═O)₂—R^(B13)wherein R^(B12) and R^(B13) are the same or different and each is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group C,(k) —NR^(B14)—C(O)—OR^(B15) wherein R^(B14) is a hydrogen atom or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group C, and R^(B15) is a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group C, (l) —S(═O)₂—R^(B16)wherein R^(B16) is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group C, and (m) —S(═O)₂—OR^(B17) wherein R^(B17) is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group C,Group C is selected from the group consisting of (a) a halogen atom, (b)—C(═O)—R^(C1) wherein R^(C1) is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 halogen atoms,(c) —C(═O)—OR^(C2) wherein R^(C2) is a hydrogen atom or a C₁₋₆ alkylgroup, and (d) —OR^(C3) wherein R^(C3) is a hydrogen atom or a C₁₋₆alkyl group, Group D is selected from the group consisting of (a) ahalogen atom, (b) a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group E,(c) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group F, (d) a C₁₋₆ alkyl group substituted by a C₃₋₁₀cycloalkyl optionally substituted by the same or different 1 to 5substituents selected from the following group F, (e) a C₁₋₆ alkyl groupsubstituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by thesame or different 1 to 5 substituents selected from the following groupF, (f) a C₁₋₆ alkyl group substituted by a monocyclic aromaticheterocyclic group optionally substituted by the same or different 1 to5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic groupcontains, besides carbon atom, 1 to 4 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7ring-constituting atoms), (g) a C₃₋₁₀ cycloalkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group F, (h) a C₅₋₁₀ bridged cycloalkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group F, (i) a cyano group, (j) —C(═O)—R^(D1) whereinR^(D1) is a hydrogen atom, a C₁₋₆ alkyl group optionally substituted bythe same or different 1 to 5 substituents selected from the followinggroup E, or a monocyclic non-aromatic heterocyclic group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group F (the monocyclic non-aromatic heterocyclic groupcontains, besides carbon atom, 1 to 4 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7ring-constituting atoms), (k) —C(═O)—OR^(D2) wherein R^(D2) is ahydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group E,(l) —C(═O)—NR^(D3)R^(D4) wherein R^(D3) and R^(D4) are the same ordifferent and each is a hydrogen atom, or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group E, (m) —C(═O)—NR^(D5)—OR^(D6) wherein R^(D5) andR^(D6) are the same or different and each is a hydrogen atom, or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group E, (n) —OR^(D7) whereinR^(D7) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup E, (o) —NR^(D8)R^(D9) wherein R^(D8) and R^(D9) are the same ordifferent and each is a hydrogen atom, or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group E, (p) —NR^(D)—C(═O)—R^(D11) wherein R^(D10) andR^(D11) are the same or different and each is a hydrogen atom, or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group E, (q)—NR^(D12)—C(O)—OR^(D13) wherein R^(D12) is a hydrogen atom, or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group E, and R^(D13) is a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group E, (r) —S(═O)₂—R^(D14)wherein R^(D14) is a hydrogen atom, or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group E, and (s) —S(═O)₂—OR^(D15) wherein R^(D15) is ahydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group E,Group E is selected from the group consisting of (a) a halogen atom, (b)a cyano group, (c) —C(═O)—R^(E1) wherein R^(E1) is a hydrogen atom or aC₁₋₆ alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group F, (d) —C(═O)—OR^(E2)wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group F, (e) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) andR^(E4) are the same or different and each is a hydrogen atom or a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the following group F, (f)—C(═O)—NR^(E5)—OR^(E6) wherein R^(E5) and R^(E6) are the same ordifferent and each is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group F, (g) —OR^(E7) wherein R^(E7) is a hydrogen atom ora C₁₋₆ alkyl group optionally substituted by the same or different 1 to5 substituents selected from the following group F, (h) —NR^(E8)R^(E9)wherein R^(E8) and R^(E9) are the same or different and each is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group F,(i) —NR^(E10)—C(═O)—R^(E11) wherein R^(E10) and R^(E11) are the same ordifferent and each is a hydrogen atom or a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group F, (j) —NR^(E12)—C(O)—OR^(E13) wherein R^(E12) is ahydrogen atom or a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from the following group F,and R^(E13) is a C₁₋₆ alkyl group optionally substituted by the same ordifferent 1 to 5 substituents selected from the following group F, (k)—S(═O)₂—R^(E14) wherein R^(E14) is a hydrogen atom or a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the following group F, (l) —S(═O)₂—OR^(E15) whereinR^(E15) is a hydrogen atom or a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from the followinggroup F, and (m) —NR^(E16)—S(═O)₂—R^(E17) wherein R^(E16) and R^(E17)are the same or different and each is a hydrogen atom or a C₁₋₆ alkylgroup and Group F is selected from the group consisting of (a)—(CH₂)_(nF1)—C(═O)—OR^(F1) wherein R^(F1) is a hydrogen atom or a C₁₋₆alkyl group, and nF1 is an integer of 0, or 1 to 4, and (b)—(CH₂)_(nF2)—OR^(F2) wherein R^(F2) is a hydrogen atom or a C₁₋₆ alkylgroup, and nF2 is an integer of 0, or 1 to
 4. 2. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, and a pharmaceuticallyacceptable carrier.
 3. A method of inhibiting PDHK in a mammal,comprising administering a pharmaceutically effective amount of thecompound of claim 1, or a pharmaceutically acceptable salt thereof, or asolvate thereof to the mammal.
 4. A method of inhibiting PDHK2 in amammal, comprising administering a pharmaceutically effective amount ofthe compound of claim 1, or a pharmaceutically acceptable salt thereof,or a solvate thereof to the mammal.
 5. A method of decreasing the bloodglucose level in a mammal, comprising administering a pharmaceuticallyeffective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof to the mammal.
 6. A methodof decreasing lactate level in a mammal, comprising administering apharmaceutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof, or a solvate thereof to themammal.
 7. A method for the treatment of diabetes, diabeticcomplications, insulin resistance syndrome, metabolic syndrome,hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy,pulmonary hypertension, hyperlactacidemia, mitochondrial disease,mitochondrial encephalomyopathy or cancer in mammal, comprisingadministering a pharmaceutically effective amount of the compound ofclaim 1, or a pharmaceutically acceptable salt thereof, or a solvatethereof to the mammal.